Health Education

Schistosomiasis

2016-02-24T05:48:00.000-08:00

Note

Schistosomiasis is an acute and chronic disease caused by parasitic worms.
People are infected during routine agricultural, domestic, occupational and recreational activities which expose them to infested water.

Lack of hygiene and certain play habits of school-aged children such as swimming or fishing in infested water make them especially vulnerable to infection.
Schistosomiasis control focuses on reducing disease through periodic, large-scale population treatment with praziquantel; a more comprehensive approach including potable water, adequate sanitation and snail control would also reduce transmission.
Estimates show that at least 258 million people required preventive treatment for schistosomiasis in 2014.
More than 61.6 million people were reported to have been treated for schistosomiasis in 2014.

Schistosomiasis is an acute and chronic parasitic disease caused by blood flukes (trematode worms) of the genus Schistosoma. Estimates show that at least 258 million people required preventive treatment in 2014. Preventive treatment, which should be repeated over a number of years, will reduce and prevent morbidity. Schistosomiasis transmission has been reported from 78 countries. However, preventive chemotherapy for schistosomiasis, where people and communities are targeted for large scale treatment, is only required in 52 endemic countries with moderate to high transmission.

Transmission

Transmission occurs when people suffering from schistosomiasis contaminate freshwater sources with their excreta containing parasite eggs which hatch in water.
People become infected when larval forms of the parasite – released by freshwater snails – penetrate the skin during contact with infested water.
In the body, the larvae develop into adult schistosomes. Adult worms live in the blood vessels where the females release eggs. Some of the eggs are passed out of the body in the faeces or urine to continue the parasite’s life-cycle. Others become trapped in body tissues, causing immune reactions and progressive damage to organs.

Epidemiology

Schistosomiasis is prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. It is estimated that at least 90% of those requiring treatment for schistosomiasis live in Africa.
There are two major forms of schistosomiasis – intestinal and urogenital – caused by five main species of blood fluke (see table).

Table: Parasite species and geographical distribution of schistosomiasis

	Species	Geographical distribution
Intestinal schistosomiasis	Schistosoma mansoni	Africa, the Middle East, the Caribbean, Brazil, Venezuela and Suriname
	Schistosoma japonicum	China, Indonesia, the Philippines
	Schistosoma mekongi	Several districts of Cambodia and the Lao People’s Democratic Republic
	Schistosoma guineensisand related S. intercalatum	Rain forest areas of central Africa
Urogenital schistosomiasis	Schistosoma haematobium	Africa, the Middle East, Corsica (France)

Schistosomiasis mostly affects poor and rural communities, particularly agricultural and fishing populations. Women doing domestic chores in infested water, such as washing clothes, are also at risk. Inadequate hygiene and contact with infected water make children especially vulnerable to infection.
Migration to urban areas and population movements are introducing the disease to new areas. Increasing population size and the corresponding needs for power and water often result in development schemes, and environmental modifications facilitate transmission.
With the rise in eco-tourism and travel “off the beaten track”, increasing numbers of tourists are contracting schistosomiasis. At times, tourists present with severe acute infection and unusual problems including paralysis.
Urogenital schistosomiasis is also considered to be a risk factor for HIV infection, especially in women.

Symptoms

Symptoms of schistosomiasis are caused by the body’s reaction to the worms’ eggs.
Intestinal schistosomiasis can result in abdominal pain, diarrhoea and blood in the stool. Liver enlargement is common in advanced cases, and is frequently associated with an accumulation of fluid in the peritoneal cavity and hypertension of the abdominal blood vessels. In such cases there may also be enlargement of the spleen.
The classic sign of urogenital schistosomiasis is haematuria (blood in urine). Fibrosis of the bladder and ureter, and kidney damage are sometimes diagnosed in advanced cases. Bladder cancer is another possible complication in the later stages. In women, urogenital schistosomiasis may present with genital lesions, vaginal bleeding, pain during sexual intercourse and nodules in the vulva. In men, urogenital schistosomiasis can induce pathology of the seminal vesicles, prostate and other organs. This disease may also have other long-term irreversible consequences, including infertility.
The economic and health effects of schistosomiasis are considerable and the disease disables more than it kills. In children, schistosomiasis can cause anaemia, stunting and a reduced ability to learn, although the effects are usually reversible with treatment. Chronic schistosomiasis may affect people’s ability to work and in some cases can result in death.¹ The number of deaths due to schistosomiasis is difficult to estimate because of hidden pathologies such as liver and kidney failure and bladder cancer. Estimates therefore vary widely between 20 000 and 200 000 deaths per year.

Diagnosis

Schistosomiasis is diagnosed through the detection of parasite eggs in stool or urine specimens. Antibodies and/or antigens detected in blood or urine samples are also indications of infection.
For urogenital schistosomiasis, a filtration technique using nylon, paper or polycarbonate filters is the standard diagnostic technique. Children with S. haematobium almost always have microscopic blood in their urine and this can be detected by chemical reagent strips.
The eggs of intestinal schistosomiasis can be detected in faecal specimens through a technique using methylene blue-stained cellophane soaked in glycerine or glass slides, known as the Kato-Katz technique.
For people living in non-endemic or low-transmission areas, serological and immunological tests may be useful in showing exposure to infection and the need for thorough examination, treatment and follow-up.

Prevention and control

The control of schistosomiasis is based on large-scale treatment of at-risk population groups, access to safe water, improved sanitation, hygiene education and snail control.
The WHO strategy for schistosomiasis control focuses on reducing disease through periodic, targeted treatment with praziquantel through the large-scale treatment (preventive chemotherapy) of affected populations. It involves regular treatment of all at-risk groups. In a few countries, where there is low transmission, the elimination of the disease should be aimed for.
Groups targeted for treatment are:

school-aged children in endemic areas,
adults considered to be at risk in endemic areas, and people with occupations involving contact with infested water, such as fishermen, farmers, irrigation workers, and women whose domestic tasks bring them in contact with infested water,
entire communities living in highly endemic areas.

The frequency of treatment is determined by the prevalence of infection in school-age children. In high-transmission areas, treatment may have to be repeated every year for a number of years. Monitoring is essential to determine the impact of control interventions.
The aim is to reduce disease: periodic treatment of at-risk populations will cure mild symptoms and prevent infected people from developing severe, late-stage chronic disease. However, a major limitation to schistosomiasis control has been the limited availability of praziquantel. Data for 2014 show that 20.7% of people requiring treatment were reached.
Praziquantel is the recommended treatment against all forms of schistosomiasis. It is effective, safe and low-cost. Even though re-infection may occur after treatment, the risk of developing severe disease is diminished and even reversed when treatment is initiated and repeated in childhood.
Schistosomiasis control has been successfully implemented over the past 40 years in several countries, including Brazil, Cambodia, China, Egypt, Mauritius, Islamic Republic of Iran and Saudi Arabia. There is evidence that schistosomiasis transmission was interrupted in Morocco. In Burkina Faso, Niger, Sierra Leone and Yemen, it has been possible to scale up schistosomiasis treatment to the national level and have an impact on the disease in a few years. An assessment of the status of transmission is being made in several countries.
Over the past 10 years, there has been scale-up of treatment campaigns in a number of sub-Saharan countries, where most of those at risk live.

Cardiovascular diseases (CVDs)

2016-02-24T05:18:00.000-08:00

Note

CVDs are the number 1 cause of death globally: more people die annually from CVDs than from any other cause.
An estimated 17.5 million people died from CVDs in 2012, representing 31% of all global deaths. Of these deaths, an estimated 7.4 million were due to coronary heart disease and 6.7 million were due to stroke .
Over three quarters of CVD deaths take place in low- and middle-income countries.
Out of the 16 million deaths under the age of 70 due to noncommunicable diseases, 82% are in low and middle income countries and 37% are caused by CVDs.
Most cardiovascular diseases can be prevented by addressing behavioural risk factors such as tobacco use, unhealthy diet and obesity, physical inactivity and harmful use of alcohol using population-wide strategies.
People with cardiovascular disease or who are at high cardiovascular risk (due to the presence of one or more risk factors such as hypertension, diabetes, hyperlipidaemia or already established disease) need early detection and management using counselling and medicines, as appropriate.

What are cardiovascular diseases?

Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels and they include:

coronary heart disease – disease of the blood vessels supplying the heart muscle;
cerebrovascular disease – disease of the blood vessels supplying the brain;
peripheral arterial disease – disease of blood vessels supplying the arms and legs;
rheumatic heart disease – damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria;
congenital heart disease – malformations of heart structure existing at birth;
deep vein thrombosis and pulmonary embolism – blood clots in the leg veins, which can dislodge and move to the heart and lungs.

Heart attacks and strokes are usually acute events and are mainly caused by a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding from a blood vessel in the brain or from blood clots. The cause of heart attacks and strokes are usually the presence of a combination of risk factors, such as tobacco use, unhealthy diet and obesity, physical inactivity and harmful use of alcohol, hypertension, diabetes and hyperlipidaemia.

What are the risk factors for cardiovascular disease?

The most important behavioural risk factors of heart disease and stroke are unhealthy diet, physical inactivity, tobacco use and harmful use of alcohol. The effects of behavioural risk factors may show up in individuals as raised blood pressure, raised blood glucose, raised blood lipids, and overweight and obesity. These “intermediate risks factors” can be measured in primary care facilities and indicate an increased risk of developing a heart attack, stroke, heart failure and other complications.
Cessation of tobacco use, reduction of salt in the diet, consuming fruits and vegetables, regular physical activity and avoiding harmful use of alcohol have been shown to reduce the risk of cardiovascular disease. In addition, drug treatment of diabetes, hypertension and high blood lipids may be necessary to reduce cardiovascular risk and prevent heart attacks and strokes. Health policies that create conducive environments for making healthy choices affordable and available are essential for motivating people to adopt and sustain healthy behaviour.
There are also a number of underlying determinants of CVDs or "the causes of the causes". These are a reflection of the major forces driving social, economic and cultural change – globalization, urbanization and population ageing. Other determinants of CVDs include poverty, stress and hereditary factors.

What are common symptoms of cardiovascular diseases?

Symptoms of heart attacks and strokes

Often, there are no symptoms of the underlying disease of the blood vessels. A heart attack or stroke may be the first warning of underlying disease. Symptoms of a heart attack include:

pain or discomfort in the centre of the chest;
pain or discomfort in the arms, the left shoulder, elbows, jaw, or back.

In addition the person may experience difficulty in breathing or shortness of breath; feeling sick or vomiting; feeling light-headed or faint; breaking into a cold sweat; and becoming pale. Women are more likely to have shortness of breath, nausea, vomiting, and back or jaw pain.
The most common symptom of a stroke is sudden weakness of the face, arm, or leg, most often on one side of the body. Other symptoms include sudden onset of:

numbness of the face, arm, or leg, especially on one side of the body;
confusion, difficulty speaking or understanding speech;
difficulty seeing with one or both eyes;
difficulty walking, dizziness, loss of balance or coordination;
severe headache with no known cause; and
fainting or unconsciousness.

People experiencing these symptoms should seek medical care immediately.

What is rheumatic heart disease?

Rheumatic heart disease is caused by damage to the heart valves and heart muscle from the inflammation and scarring caused by rheumatic fever. Rheumatic fever is caused by an abnormal response of the body to infection with streptococcal bacteria, which usually begins as a sore throat or tonsillitis in children.
Rheumatic fever mostly affects children in developing countries, especially where poverty is widespread. Globally, about 2% of deaths from cardiovascular diseases is related to rheumatic heart disease.

Symptoms of rheumatic heart disease

Symptoms of rheumatic heart disease include: shortness of breath, fatigue, irregular heart beats, chest pain and fainting.
Symptoms of rheumatic fever include: fever, pain and swelling of the joints, nausea, stomach cramps and vomiting.

Why are cardiovascular diseases a development issue in low- and middle-income countries?

At least three quarters of the world's deaths from CVDs occur in low- and middle-income countries.
People in low- and middle-income countries often do not have the benefit of integrated primary health care programmes for early detection and treatment of people with risk factors compared to people in high-income countries.
People in low- and middle-income countries who suffer from CVDs and other noncommunicable diseases have less access to effective and equitable health care services which respond to their needs. As a result, many people in low- and middle-income countries are detected late in the course of the disease and die younger from CVDs and other noncommunicable diseases, often in their most productive years.
The poorest people in low- and middle-income countries are affected most. At the household level, sufficient evidence is emerging to prove that CVDs and other noncommunicable diseases contribute to poverty due to catastrophic health spending and high out-of-pocket expenditure.
At macro-economic level, CVDs place a heavy burden on the economies of low- and middle-income countries.

How can the burden of cardiovascular diseases be reduced?

“Best buys” or very cost effective interventions that are feasible to be implemented even in low-resource settings have been identified by WHO for prevention and control of cardiovascular diseases. They include two types of interventions: population-wide and individual, which are recommended to be used in combination to reduce the greatest cardiovascular disease burden.
Examples of population-wide interventions that can be implemented to reduce CVDs include:

comprehensive tobacco control policies
taxation to reduce the intake of foods that are high in fat, sugar and salt
building walking and cycle paths to increase physical activity
strategies to reduce harmful use of alcohol
providing healthy school meals to children.

At the individual level, for prevention of first heart attacks and strokes, individual health-care interventions need to be targeted to those at high total cardiovascular risk or those with single risk factor levels above traditional thresholds, such as hypertension and hypercholesterolemia. The former approach is more cost-effective than the latter and has the potential to substantially reduce cardiovascular events. This approach is feasible in primary care in low-resource settings, including by non-physician health workers.
For secondary prevention of cardiovascular disease in those with established disease, including diabetes, treatment with the following medications are necessary:

aspirin
beta-blockers
angiotensin-converting enzyme inhibitors
statins.

The benefits of these interventions are largely independent, but when used together with smoking cessation, nearly 75% of recurrent vascular events may be prevented. Currently there are major gaps in the implementation of these interventions particularly at the primary health care level.
In addition costly surgical operations are sometimes required to treat CVDs. They include:

coronary artery bypass
balloon angioplasty (where a small balloon-like device is threaded through an artery to open the blockage)
valve repair and replacement
heart transplantation
artificial heart operations

Medical devices are required to treat some CVDs. Such devices include pacemakers, prosthetic valves, and patches for closing holes in the heart.

Cholera

2016-02-24T04:49:00.001-08:00

Notes

Cholera is an acute diarrhoeal disease that can kill within hours if left untreated.
Researchers have estimated that there are 1.4 to 4.3 million cases, and 28 000 to 142 000 deaths worldwide¹ due to cholera every year.
Up to 80% of cases can be successfully treated with oral rehydration salts.
Provision of safe water and sanitation is critical to control cholera and other waterborne diseases.
Oral cholera vaccines are an additional way to control cholera, but should not replace conventional control measures.

Cholera is an acute diarrhoeal infection caused by ingestion of food or water contaminated with the bacterium Vibrio cholerae. Researchers have estimated that every year, there are roughly 1.4 to 4.3 million cases, and 28 000 to 142 000 deaths per year worldwide¹ due to cholera. The short incubation period of 2 hours to 5 days, is 1 factor that triggers the potentially explosive pattern of outbreaks.

Symptoms

Cholera is an extremely virulent disease. It affects both children and adults and can kill within hours.
About 80% of people infected with V. cholerae do not develop any symptoms, although the bacteria are present in their faeces for 1-10 days after infection and are shed back into the environment, potentially infecting other people.
Among people who develop symptoms, 80% have mild or moderate symptoms, while around 20% develop acute watery diarrhoea with severe dehydration. This can lead to death if left untreated.

History

During the 19th century, cholera spread across the world from its original reservoir in the Ganges delta in India. Six subsequent pandemics killed millions of people across all continents. The current (seventh) pandemic started in South Asia in 1961, and reached Africa in 1971 and the Americas in 1991. Cholera is now endemic in many countries.

Vibrio cholerae strains

Two serogroups of V. cholerae – O1 and O139 – cause outbreaks. V. cholerae O1 causes the majority of outbreaks, while O139 – first identified in Bangladesh in 1992 – is confined to South-East Asia.
Non-O1 and non-O139 V. cholerae can cause mild diarrhoea but do not generate epidemics.
Recently, new variant strains have been detected in several parts of Asia and Africa. Observations suggest that these strains cause more severe cholera with higher case fatality rates. Careful epidemiological monitoring of circulating strains is recommended.
The main reservoirs of V. cholerae are people and aquatic sources such as brackish water and estuaries, often associated with algal blooms. Recent studies indicate that global warming creates a favourable environment for the bacteria.

Risk factors and disease burden

Cholera transmission is closely linked to inadequate environmental management. Typical at-risk areas include peri-urban slums, where basic infrastructure is not available, as well as camps for internally displaced persons or refugees, where minimum requirements of clean water and sanitation are not met.
The consequences of a humanitarian crisis – such as disruption of water and sanitation systems, or the displacement of populations to inadequate and overcrowded camps – can increase the risk of cholera transmission should the bacteria be present or introduced. Dead bodies have never been reported as the source of epidemics.
Cholera remains a global threat to public health and a key indicator of lack of social development.
The number of cholera cases reported to WHO continues to be high. During 2013, a total of 129 064 cases were notified from 47 countries, including 2102 deaths. The discrepancy between those figures and the estimated burden of the disease is due to the fact that many cases are not recorded for due to limitations in surveillance systems and fear of trade and travel sanctions.

Prevention and control

A multidisciplinary approach is key for reducing cholera outbreaks, controlling cholera in endemic areas and reducing deaths.

Water and sanitation interventions

The long-term solution for cholera control (which benefits all diseases spread by the fecal-oral route) lies in economic development and universal access to safe drinking water and adequate sanitation, which is key in preventing both epidemic and endemic cholera.
Actions targeting environmental conditions include:

the development of piped water systems with water treatment facilities (chlorination);
interventions at the household level (water filtration, water chemical or solar disinfection, safe water storage containers); and
as well as the construction of systems for sewage disposal and latrines.

Most of those interventions require substantial long term investments and high maintenance costs which are difficult to fund and sustain by the least developed countries, where they are also most needed.

Treatment

Cholera is an easily treatable disease. Up to 80% of people can be treated successfully through prompt administration of oral rehydration salts (WHO/UNICEF ORS standard sachet). Very severely dehydrated patients require the administration of intravenous fluids. These patients also need appropriate antibiotics to diminish the duration of diarrhoea, reduce the volume of rehydration fluids needed, and shorten the duration of V. cholerae excretion. Mass administration of antibiotics is not recommended, as it has no effect on the spread of cholera and contributes to increasing antimicrobial resistance.
In order to ensure timely access to treatment, cholera treatment centres (CTCs) should be set up within the affected communities. With proper treatment, the case fatality rate should remain below 1%.

Surveillance

Under the International Health Regulations, notification of all cases of cholera is no longer mandatory. However, public health events involving cholera must always be assessed against the criteria provided in the Regulations to determine whether there is a need for official notification.
Local capacities for improving diagnosis, and for collecting, compiling and analysing data, need to be strengthened so that vulnerable populations living in high-risk areas can be identified in order to benefit from comprehensive control activities. Cholera surveillance should be part of an integrated disease surveillance system that includes feedback at the local level and information-sharing at the global level.

Social mobilisation

Health education campaigns, adapted to local culture and beliefs, should promote the adoption of appropriate hygiene practices such as hand-washing with soap, safe preparation and storage of food and breastfeeding.
Awareness campaigns during outbreaks also encourage people with symptoms to seek immediate health care. The campaigns should use modern communication channels (mobile phones, smartphones, social media, etc.) and adapted to local cultures. The use of qualitative methods of analysis, to help adapt messages to local culture and beliefs, is also encouraged.

Oral cholera vaccines

Currently there are 2 WHO pre-qualified oral cholera vaccines (OCVs) (Dukoral® and Shanchol®). Both vaccines have been used in mass vaccination campaigns with WHO support. Their use has enabled evidence to be collected on the effectiveness and feasibility on implementation of oral cholera vaccination campaigns as a public health tool in protecting populations at high risk of cholera.
Dukoral® is administered to adults and children aged >6 years in 2 doses; and to children aged >2 years and <6 years in 3 doses. Protection can be expected 1 week after the last dose. Field trials in Bangladesh and Peru have shown that this vaccine is safe and confers 85% protection for 4–6 months in all age groups. This vaccine is not licensed for use in children aged <2 years.
Shanchol’s immunization schedule is 2 doses given at an interval of 2 weeks for those aged >1 year. Shanchol® has provided longer term protection than Dukoral® in children aged <5 years, and therefore does not require a booster dose after 6 months in this age group, unlike Dukoral®. Shanchol® provided 67% protection against clinically significant V. cholerae O1 cholera in an endemic area for at least 2 years after vaccination. A field trial in Kolkata, India obtained protective efficacy (65%) of the vaccine up to 5 years.
An OCV stockpile of 2 million doses was formally established mid-2013 for outbreak control and emergencies. The OCV stockpile was created on the principle that vaccines have a role in the prevention and control of cholera when used in conjunction with accessible healthcare and improvements in water and sanitation.
In November 2013, the GAVI board approved a contribution to the global cholera vaccine stockpile for epidemic and endemic settings, for 2014-2018. The objectives of the GAVI investment are to:

break the current cycle of low demand–low supply, significantly increasing global OCV production and availability;
reduce the impact of cholera outbreaks; and
strengthen the evidence base for periodic pre-emptive campaigns.

As of June 2015, about 2 million doses of OCV have been shipped from the stockpile in various settings, either in the form of reactive campaigns in areas experiencing an outbreak or pre-emptive vaccination campaigns among populations at elevated risk for cholera (“hotspots”), or at heightened vulnerability during an humanitarian crisis.
Impact on cholera burden or transmission was significant in all endemic, outbreak and emergency settings. Furthermore, contrary to earlier concerns, the communities readily accepted the vaccines and high vaccine coverage were reported. No serious adverse effects have been reported so far.

Travel and trade

Today, no country requires proof of cholera vaccination as a condition for entry. Past experience shows that quarantine measures and embargoes on the movement of people and goods are unnecessary. Import restrictions on food produced using good manufacturing practices, based on the sole fact that cholera is epidemic or endemic in a country, are not justified.
Countries neighbouring cholera-affected areas are encouraged to strengthen disease surveillance and national preparedness to rapidly detect and respond to outbreaks should cholera spread across borders. Further, information should be provided to travellers and the community on the potential risks and symptoms of cholera, together with precautions to avoid cholera, and when and where to report cases.

Meningococcal meningitis

2016-02-24T03:38:00.000-08:00

Notes

Meningococcal meningitis is a bacterial form of meningitis, a serious infection of the thin lining that surrounds the brain and spinal cord.
The extended meningitis belt of sub-Saharan Africa, stretching from Senegal in the west to Ethiopia in the east (26 countries), has the highest rates of the disease.
Before 2010 and the mass preventive immunization campaigns, Group A meningococcus accounted for an estimated 80–85% of all cases in the meningitis belt, with epidemics occurring at intervals of 7–14 years. Since then, the proportion of the A serogroup has declined dramatically.
During the 2014 epidemic season, 19 African countries implementing enhanced surveillance reported 11 908 suspected cases including 1146 deaths, the lowest numbers since the implementation of enhanced surveillance through a functional network (2004).
Several vaccines are available to control the disease: a meningococcal A conjugate vaccine, C conjugate vaccines, tetravalent A, C, Y and W conjugate vaccines and meningococcal polysaccharide vaccines.
As of June 2015, over 220 million persons aged 1 to 29 years have received meningococcal A conjugate vaccine in 15 countries of the African belt.

Meningococcal meningitis is a bacterial form of meningitis, a serious infection of the meninges that affects the brain membrane. It can cause severe brain damage and is fatal in 50% of cases if untreated.
Several different bacteria can cause meningitis. Neisseria meningitidis is the one with the potential to cause large epidemics. There are 12 serogroups of N. meningitidis that have been identified, 6 of which (A, B, C, W, X and Y) can cause epidemics. Geographic distribution and epidemic potential differ according to serogroup.

Transmission

The bacteria are transmitted from person-to-person through droplets of respiratory or throat secretions from carriers. Close and prolonged contact – such as kissing, sneezing or coughing on someone, or living in close quarters (such as a dormitory, sharing eating or drinking utensils) with an infected person (a carrier) – facilitates the spread of the disease. The average incubation period is 4 days, but can range between 2 and 10 days.
Neisseria meningitidis only infects humans; there is no animal reservoir. The bacteria can be carried in the throat and sometimes, for reasons not fully understood, can overwhelm the body's defenses allowing infection to spread through the bloodstream to the brain. It is believed that 10% to 20% of the population carries Neisseria meningitidis in their throat at any given time. However, the carriage rate may be higher in epidemic situations.

Symptoms

The most common symptoms are a stiff neck, high fever, sensitivity to light, confusion, headaches and vomiting. Even when the disease is diagnosed early and adequate treatment is started, 5% to 10% of patients die, typically within 24 to 48 hours after the onset of symptoms. Bacterial meningitis may result in brain damage, hearing loss or a learning disability in 10% to 20% of survivors. A less common but even more severe (often fatal) form of meningococcal disease is meningococcal septicaemia, which is characterized by a haemorrhagic rash and rapid circulatory collapse.

Diagnosis

Initial diagnosis of meningococcal meningitis can be made by clinical examination followed by a lumbar puncture showing a purulent spinal fluid. The bacteria can sometimes be seen in microscopic examinations of the spinal fluid. The diagnosis is supported or confirmed by growing the bacteria from specimens of spinal fluid or blood, by agglutination tests or by polymerase chain reaction (PCR). The identification of the serogroups and susceptibility testing to antibiotics are important to define control measures.

Treatment

Meningococcal disease is potentially fatal and should always be viewed as a medical emergency. Admission to a hospital or health centre is necessary, although isolation of the patient is not necessary. Appropriate antibiotic treatment must be started as soon as possible, ideally after the lumbar puncture has been carried out if such a puncture can be performed immediately. If treatment is started prior to the lumbar puncture it may be difficult to grow the bacteria from the spinal fluid and confirm the diagnosis.
A range of antibiotics can treat the infection, including penicillin, ampicillin, chloramphenicol and ceftriaxone. Under epidemic conditions in Africa in areas with limited health infrastructure and resources, ceftriaxone is the drug of choice.

Prevention

There are 3 types of vaccines available.

Polysaccharide vaccines have been available to prevent the disease for over 30 years. Meningococcal polysaccharide vaccines are available in either bivalent (groups A and C), trivalent (groups A, C and W), or tetravalent (groups A, C, Y and W) forms to control the disease.
For group B, polysaccharide vaccines cannot be developed, due to antigenic mimicry with polysaccharide in human neurologic tissues. The first vaccine against NmB, made from a combination of 4 protein components, was released in 2014.
Since 1999, meningococcal conjugate vaccines against group C have been available and widely used. Tetravalent A, C, Y and W conjugate vaccines have been licensed since 2005 for use in children and adults in Canada, the United States of America, and Europe.

The extended meningitis belt of sub-Saharan Africa, stretching from Senegal in the west to Ethiopia in the east (26 countries), has the highest rates of the disease. The 26 countries include: Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Côte d’Ivoire, Democratic Republic of Congo, Eritrea, Ethiopia, The Gambia, Ghana, Guinea, Guinea Bissau, Kenya, Mali, Mauritania, Niger, Nigeria, Rwanda, Senegal, South Sudan, Sudan, Tanzania, Togo and Uganda. The risk of meningococcal meningitis epidemics differs within and among these 26 countries.
In December 2010, a new meningococcal A conjugate vaccine was introduced nationwide in Burkina Faso, and in selected regions of Mali and Niger (the remaining regions were covered in 2011), targeting persons 1 to 29 years of age. As of June 2015, 220 million persons have been vaccinated with this vaccine in 16 countries (Benin, Burkina Faso, Cameroon, Chad, Côte d’Ivoire, Ethiopia, The Gambia, Ghana, Guinea, Mali, Mauritania, Niger, Nigeria, Senegal, Sudan, and Togo).
The MenA conjugate vaccine has several advantages over existing polysaccharide vaccines:

it induces a higher and more sustainable immune response against group A meningococcus;
it reduces the carriage of the bacteria in the throat and thus its transmission;
it is expected to confer long-term protection not only for those who receive the vaccine, but on family members and others who would otherwise have been exposed to meningitis;
it is available at a lower price than other meningococcal vaccines (around 0.50 USD per dose, other meningococcal vaccine prices range from 2.50 USD to 117.00 USD per dose); and
it is expected to be particularly effective in protecting children under two years of age, who do not respond to conventional polysaccharide vaccines.

In addition, its thermostability allows for a use under Controlled Temperature Chain (CTC) conditions. More than 2 million persons in 4 countries have been vaccinated without ice use at the vaccination site.
It is planned that all 26 African countries considered at risk for meningitis epidemics and targeted by this vaccine introduction programme will have introduced this vaccine by 2016. High coverage of the target age group of 1–29 years is expected to eliminate meningococcal A epidemics from this region of Africa.

Outbreak trends

Meningococcal meningitis occurs in small clusters throughout the world with seasonal variation and accounts for a variable proportion of epidemic bacterial meningitis.
The largest burden of meningococcal disease occurs in an area of sub-Saharan Africa known as the meningitis belt, which stretches from Senegal in the west to Ethiopia in the east. During the dry season between December to June, dust winds, cold nights and upper respiratory tract infections combine to damage the nasopharyngeal mucosa, increasing the risk of meningococcal disease. At the same time, transmission of N. meningitidis may be facilitated by overcrowded housing and by large population displacements at the regional level due to pilgrimages and traditional markets. This combination of factors explains the large epidemics which occur during the dry season in the meningitis belt.
Following the successful roll-out of the MenA conjugate vaccine, epidemics due to N. meningitidis serogroup A are disappearing, but other meningococcal serogroups such as NmW, NmX and NmC still cause epidemics albeit at a lower frequency and smaller size.

Zika virus

2016-02-20T13:38:00.001-08:00

Facts

Zika virus disease is caused by a virus transmitted by Aedes mosquitoes.
People with Zika virus disease usually have symptoms that can include mild fever, skin rashes, conjunctivitis, muscle and joint pain, malaise or headache. These symptoms normally last for 2-7 days.
There is no specific treatment or vaccine currently available.
The best form of prevention is protection against mosquito bites.
The virus is known to circulate in Africa, the Americas, Asia and the Pacific.

Introduction

Zika virus is an emerging mosquito-borne virus that was first identified in Uganda in 1947 in rhesus monkeys through a monitoring network of sylvatic yellow fever. It was subsequently identified in humans in 1952 in Uganda and the United Republic of Tanzania. Outbreaks of Zika virus disease have been recorded in Africa, the Americas, Asia and the Pacific.

Genre: Flavivirus
Vector: Aedes mosquitoes (which usually bite during the morning and late afternoon/evening hours)
Reservoir: Unknown

Signs and Symptoms

The incubation period (the time from exposure to symptoms) of Zika virus disease is not clear, but is likely to be a few days. The symptoms are similar to other arbovirus infections such as dengue, and include fever, skin rashes, conjunctivitis, muscle and joint pain, malaise, and headache. These symptoms are usually mild and last for 2-7 days.

Potential complications of Zika virus disease

During large outbreaks in French Polynesia and Brazil in 2013 and 2015 respectively, national health authorities reported potential neurological and auto-immune complications of Zika virus disease. Recently in Brazil, local health authorities have observed an increase in Guillain-Barré syndrome which coincided with Zika virus infections in the general public, as well as an increase in babies born with microcephaly in northeast Brazil. Agencies investigating the Zika outbreaks are finding an increasing body of evidence about the link between Zika virus and microcephaly. However, more investigation is needed to better understand the relationship between microcephaly in babies and the Zika virus. Other potential causes are also being investigated.

Transmission

Zika virus is transmitted to people through the bite of an infected mosquito from the Aedes genus, mainly Aedes aegypti in tropical regions. This is the same mosquito that transmits dengue, chikungunya and yellow fever. However, sexual transmission of Zika virus has been described in 2 cases, and the presence of the Zika virus in semen in 1 additional case.
Zika virus disease outbreaks were reported for the first time from the Pacific in 2007 and 2013 (Yap and French Polynesia, respectively), and in 2015 from the Americas (Brazil and Colombia) and Africa (Cape Verde). In addition, more than 13 countries in the Americas have reported sporadic Zika virus infections indicating rapid geographic expansion of Zika virus.

Diagnosis

Infection with Zika virus may be suspected based on symptoms and recent history (e.g. residence or travel to an area where Zika virus is known to be present). Zika virus diagnosis can only be confirmed by laboratory testing for the presence of Zika virus RNA in the blood or other body fluids, such as urine or saliva.

Prevention

Mosquitoes and their breeding sites pose a significant risk factor for Zika virus infection. Prevention and control relies on reducing mosquitoes through source reduction (removal and modification of breeding sites) and reducing contact between mosquitoes and people.
This can be done by using insect repellent regularly; wearing clothes (preferably light-coloured) that cover as much of the body as possible; using physical barriers such as window screens, closed doors and windows; and if needed, additional personal protection, such as sleeping under mosquito nets during the day. It is extremely important to empty, clean or cover containers regularly that can store water, such as buckets, drums, pots etc. Other mosquito breeding sites should be cleaned or removed including flower pots, used tyres and roof gutters. Communities must support the efforts of the local government to reduce the density of mosquitoes in their locality.
Repellents should contain DEET (N, N-diethyl-3-methylbenzamide), IR3535 (3-[N-acetyl-N-butyl]-aminopropionic acid ethyl ester) or icaridin (1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)-1-methylpropylester). Product label instructions should be strictly followed. Special attention and help should be given to those who may not be able to protect themselves adequately, such as young children, the sick or elderly.
During outbreaks, health authorities may advise that spraying of insecticides be carried out. Insecticides recommended by the WHO Pesticide Evaluation Scheme may also be used as larvicides to treat relatively large water containers.
Travellers should take the basic precautions described above to protect themselves from mosquito bites.

Treatment

Zika virus disease is usually relatively mild and requires no specific treatment. People sick with Zika virus should get plenty of rest, drink enough fluids, and treat pain and fever with common medicines. If symptoms worsen, they should seek medical care and advice. There is currently no vaccine available.

MALARIA

2016-02-20T13:01:00.001-08:00

Key facts

Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female mosquitoes.
About 3.2 billion people – almost half of the world’s population – are at risk of malaria.
Young children, pregnant women and non-immune travellers from malaria-free areas are particularly vulnerable to the disease when they become infected.
Malaria is preventable and curable, and increased efforts are dramatically reducing the malaria burden in many places.
Between 2000 and 2015, malaria incidence among populations at risk (the rate of new cases) fell by 37% globally. In that same period, malaria death rates among populations at risk fell by 60% globally among all age groups, and by 65% among children under 5.
Sub-Saharan Africa carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 88% of malaria cases and 90% of malaria deaths.

Malaria is caused by Plasmodium parasites. The parasites are spread to people through the bites of infected female Anopheles mosquitoes, called "malaria vectors." There are 5 parasite species that cause malaria in humans, and 2 of these species – P. falciparum and P. vivax – pose the greatest threat.

P. falciparum is the most prevalent malaria parasite on the African continent. It is responsible for most malaria-related deaths globally.
P. vivax has a wider distribution than P. falciparum, and predominates in many countries outside of Africa.

Symptoms

Malaria is an acute febrile illness. In a non-immune individual, symptoms appear 7 days or more (usually 10–15 days) after the infective mosquito bite. The first symptoms – fever, headache, chills and vomiting – may be mild and difficult to recognize as malaria. If not treated within 24 hours, P. falciparum malaria can progress to severe illness, often leading to death.
Children with severe malaria frequently develop one or more of the following symptoms: severe anaemia, respiratory distress in relation to metabolic acidosis, or cerebral malaria. In adults, multi-organ involvement is also frequent. In malaria endemic areas, people may develop partial immunity, allowing asymptomatic infections to occur.

Who is at risk?

In 2015, approximately 3.2 billion people – nearly half of the world's population – were at risk of malaria. Most malaria cases and deaths occur in sub-Saharan Africa. However, Asia, Latin America, and, to a lesser extent, the Middle East, are also at risk. In 2015, 97 countries and territories had ongoing malaria transmission.
Some population groups are at considerably higher risk of contracting malaria, and developing severe disease, than others. These include infants, children under 5 years of age, pregnant women and patients with HIV/AIDS, as well as non-immune migrants, mobile populations and travellers. National malaria control programmes need to take special measures to protect these population groups from malaria infection, taking into consideration their specific circumstances.

Disease burden

According to the latest WHO estimates, released in December 2015, there were 214 million cases of malaria in 2015 and 438 000 deaths.
Between 2000 and 2015, malaria incidence among populations at risk fell by 37% globally; during the same period, malaria mortality rates among populations at risk decreased by 60%. An estimated 6.2 million malaria deaths have been averted globally since 2001.
Sub-Saharan Africa continues to carry a disproportionately high share of the global malaria burden. In 2015, the region was home to 88% of malaria cases and 90% of malaria deaths.
Some 15 countries – mainly in sub-Saharan Africa – account for 80% of malaria cases and 78% deaths globally. Since 2000, the decline in malaria incidence in these 15 countries (32%) has lagged behind that of other countries globally (53%).
In areas with high transmission of malaria, children under 5 are particularly susceptible to infection, illness and death; more than two thirds (70%) of all malaria deaths occur in this age group. Between 2000 and 2015, the under-5 malaria death rate fell by 65% globally, translating into an estimated 5.9 million child lives saved between 2001 and 2015.

Transmission

In most cases, malaria is transmitted through the bites of female Anopheles mosquitoes. There are more than 400 different species of Anopheles mosquito; around 30 are malaria vectors of major importance. All of the important vector species bite between dusk and dawn. The intensity of transmission depends on factors related to the parasite, the vector, the human host, and the environment.
Anopheles mosquitoes lay their eggs in water, which hatch into larvae, eventually emerging as adult mosquitoes. The female mosquitoes seek a blood meal to nurture their eggs. Each species of Anopheles mosquito has its own preferred aquatic habitat; for example, some prefer small, shallow collections of fresh water, such as puddles and hoof prints, which are abundant during the rainy season in tropical countries.
Transmission is more intense in places where the mosquito lifespan is longer (so that the parasite has time to complete its development inside the mosquito) and where it prefers to bite humans rather than other animals. The long lifespan and strong human-biting habit of the African vector species is the main reason why nearly 90% of the world's malaria cases are in Africa.
Transmission also depends on climatic conditions that may affect the number and survival of mosquitoes, such as rainfall patterns, temperature and humidity. In many places, transmission is seasonal, with the peak during and just after the rainy season. Malaria epidemics can occur when climate and other conditions suddenly favour transmission in areas where people have little or no immunity to malaria. They can also occur when people with low immunity move into areas with intense malaria transmission, for instance to find work, or as refugees.
Human immunity is another important factor, especially among adults in areas of moderate or intense transmission conditions. Partial immunity is developed over years of exposure, and while it never provides complete protection, it does reduce the risk that malaria infection will cause severe disease. For this reason, most malaria deaths in Africa occur in young children, whereas in areas with less transmission and low immunity, all age groups are at risk.

Prevention

Vector control is the main way to prevent and reduce malaria transmission. If coverage of vector control interventions within a specific area is high enough, then a measure of protection will be conferred across the community.
WHO recommends protection for all people at risk of malaria with effective malaria vector control. Two forms of vector control – insecticide-treated mosquito nets and indoor residual spraying – are effective in a wide range of circumstances.

Insecticide-treated mosquito nets (ITNs)

Long-lasting insecticidal nets (LLINs) are the preferred form of ITNs for public health programmes. In most settings, WHO recommends LLIN coverage for all people at risk of malaria. The most cost-effective way to achieve this is by providing LLINs free of charge, to ensure equal access for all. In parallel, effective behaviour change communication strategies are required to ensure that all people at risk of malaria sleep under a LLIN every night, and that the net is properly maintained.

Indoor spraying with residual insecticides

Indoor residual spraying (IRS) with insecticides is a powerful way to rapidly reduce malaria transmission. Its full potential is realized when at least 80% of houses in targeted areas are sprayed. Indoor spraying is effective for 3–6 months, depending on the insecticide formulation used and the type of surface on which it is sprayed. In some settings, multiple spray rounds are needed to protect the population for the entire malaria season.
Antimalarial medicines can also be used to prevent malaria. For travellers, malaria can be prevented through chemoprophylaxis, which suppresses the blood stage of malaria infections, thereby preventing malaria disease. For pregnant women living in moderate-to-high transmission areas, WHO recommends intermittent preventive treatment with sulfadoxine-pyrimethamine, at each scheduled antenatal visit after the first trimester. Similarly, for infants living in high-transmission areas of Africa, 3 doses of intermittent preventive treatment with sulfadoxine-pyrimethamine are recommended, delivered alongside routine vaccinations.
In 2012, WHO recommended Seasonal Malaria Chemoprevention as an additional malaria prevention strategy for areas of the Sahel sub-Region of Africa. The strategy involves the administration of monthly courses of amodiaquine plus sulfadoxine-pyrimethamine to all children under 5 years of age during the high transmission season.

Insecticide resistance

Much of the success in controlling malaria is due to vector control. Vector control is highly dependent on the use of pyrethroids, which are the only class of insecticides currently recommended for ITNs or LLINs.
In recent years, mosquito resistance to pyrethroids has emerged in many countries. In some areas, resistance to all 4 classes of insecticides used for public health has been detected. Fortunately, this resistance has only rarely been associated with decreased efficacy of LLINs, which continue to provide a substantial level of protection in most settings. Rotational use of different classes of insecticides for IRS is recommended as one approach to manage insecticide resistance.
However, malaria-endemic areas of sub-Saharan Africa and India are causing significant concern due to high levels of malaria transmission and widespread reports of insecticide resistance. The use of 2 different insecticides in a mosquito net offers an opportunity to mitigate the risk of the development and spread of insecticide resistance; developing these new nets is a priority. Several promising products for both IRS and nets are in the pipeline.
Detection of insecticide resistance should be an essential component of all national malaria control efforts to ensure that the most effective vector control methods are being used. The choice of insecticide for IRS should always be informed by recent, local data on the susceptibility of target vectors.
To ensure a timely and coordinated global response to the threat of insecticide resistance, WHO worked with a wide range of stakeholders to develop the Global Plan for Insecticide Resistance Management in Malaria Vectors (GPIRM), which was released in May 2012.

Diagnosis and treatment

Early diagnosis and treatment of malaria reduces disease and prevents deaths. It also contributes to reducing malaria transmission. The best available treatment, particularly for P. falciparum malaria, is artemisinin-based combination therapy (ACT).
WHO recommends that all cases of suspected malaria be confirmed using parasite-based diagnostic testing (either microscopy or rapid diagnostic test) before administering treatment. Results of parasitological confirmation can be available in 30 minutes or less. Treatment, solely on the basis of symptoms should only be considered when a parasitological diagnosis is not possible. More detailed recommendations are available in the "WHO Guidelines for the treatment of malaria, third edition", published in April 2015.

Antimalarial drug resistance

Resistance to antimalarial medicines is a recurring problem. Resistance of P. falciparum to previous generations of medicines, such as chloroquine and sulfadoxine-pyrimethamine (SP), became widespread in the 1970s and 1980s, undermining malaria control efforts and reversing gains in child survival.
WHO recommends the routine monitoring of antimalarial drug resistance, and supports countries to strengthen their efforts in this important area of work.
An ACT contains both the drug artemisinin and a partner drug. In recent years, parasite resistance to artemisinins has been detected in 5 countries of the Greater Mekong subregion: Cambodia, Lao People’s Democratic Republic, Myanmar, Thailand and Viet Nam. Studies have confirmed that artemisinin resistance has emerged independently in many areas of this subregion. Most patients are cured when treated with an ACT if there is no resistance to the partner drug.
However, in parts of Cambodia and Thailand, P. falciparum resistance to both artemisinin and partner drugs (multi-drug resistance) has developed.
There are concerns that P. falciparum malaria in Cambodia and Thailand is becoming increasingly difficult to treat, and that multi-drug resistance could spread to other regions with dire public health consequences. Consequently, WHO’s Malaria Policy Advisory Committee in September 2014 recommended adopting the goal of eliminating P. falciparum malaria in this subregion by 2030. WHO launched the Strategy for Malaria Elimination in the Greater Mekong Subregion (2015–2030) at the World Health Assembly in May 2015, which was endorsed by all the countries in the subregion.

Surveillance

Surveillance entails tracking of the disease and programmatic responses, and taking action based on the data received. Currently many countries with a high burden of malaria have weak surveillance systems and are not in a position to assess disease distribution and trends, making it difficult to optimize responses and respond to outbreaks.
Effective surveillance is required at all points on the path to malaria elimination. Strong malaria surveillance enables programmes to optimize their operations, by empowering programmes to:

advocate for investment from domestic and international sources, commensurate with the malaria disease burden in a country or subnational area;
allocate resources to populations most in need and to interventions that are most effective, in order to achieve the greatest possible public health impact;
assess regularly whether plans are progressing as expected or whether adjustments in the scale or combination of interventions are required;
account for the impact of funding received and enable the public, their elected representatives and donors to determine if they are obtaining value for money; and
evaluate whether programme objectives have been met and learn what works so that more efficient and effective programmes can be designed.

Stronger malaria surveillance systems are urgently needed to enable a timely and effective malaria response in endemic regions, to prevent outbreaks and resurgences, to track progress, and to hold governments and the global malaria community accountable.

Elimination

Malaria elimination is defined as interrupting local mosquito-borne malaria transmission in a defined geographical area, typically countries; i.e. zero incidence of locally contracted cases. Malaria eradication is defined as the permanent reduction to zero of the worldwide incidence of malaria infection caused by a specific agent; i.e. applies to a particular malaria parasite species.
According to the latest estimates from WHO, more than half (57) of the 106 countries with malaria in 2000 had achieved reductions in new malaria cases of at least 75% by 2015, in line with targets set by the World Health Assembly. An additional 18 countries reduced their malaria cases by 50-75%.
Large-scale use of WHO-recommended strategies, currently available tools, strong national commitments, and coordinated efforts with partners, will enable more countries – particularly those where malaria transmission is low and unstable – to reduce their disease burden and progress towards elimination.
In recent years, 4 countries have been certified by the WHO Director-General as having eliminated malaria: United Arab Emirates (2007), Morocco (2010), Turkmenistan (2010), and Armenia (2011). In 2014, 16 countries reported 0 cases of malaria within their own borders. Another 17 countries reported fewer than 1000 cases of malaria.

Vaccines against malaria

There are currently no licensed vaccines against malaria or any other human parasite. One research vaccine against P. falciparum, known as RTS, S/AS01, is most advanced. This vaccine has been evaluated in a large clinical trial in 7 countries in Africa and received a positive opinion by the European Medicines Agency in July 2015.
In October 2015, 2 WHO advisory groups recommended pilot implementations of RTS,S in a limited number of African countries. These pilot projects could pave the way for wider deployment of the vaccine in 3 to 5 years, if safety and effectiveness are considered acceptable.

Ebola virus disease

2016-02-20T10:08:00.001-08:00

Facts

Ebola virus disease (EVD), formerly known as Ebola haemorrhagic fever, is a severe, often fatal illness in humans.
The virus is transmitted to people from wild animals and spreads in the human population through human-to-human transmission.
The average EVD case fatality rate is around 50%. Case fatality rates have varied from 25% to 90% in past outbreaks.
The first EVD outbreaks occurred in remote villages in Central Africa, near tropical rainforests, but the most recent outbreak in West Africa has involved major urban as well as rural areas.
Community engagement is key to successfully controlling outbreaks. Good outbreak control relies on applying a package of interventions, namely case management, surveillance and contact tracing, a good laboratory service, safe burials and social mobilisation.
Early supportive care with rehydration, symptomatic treatment improves survival. There is as yet no licensed treatment proven to neutralise the virus but a range of blood, immunological and drug therapies are under development.
There are currently no licensed Ebola vaccines but 2 potential candidates are undergoing evaluation.

Background

The Ebola virus causes an acute, serious illness which is often fatal if untreated. Ebola virus disease (EVD) first appeared in 1976 in 2 simultaneous outbreaks, one in what is now, Nzara, South Sudan, and the other in Yambuku, Democratic Republic of Congo. The latter occurred in a village near the Ebola River, from which the disease takes its name.
The current outbreak in West Africa, (first cases notified in March 2014), is the largest and most complex Ebola outbreak since the Ebola virus was first discovered in 1976. There have been more cases and deaths in this outbreak than all others combined. It has also spread between countries starting in Guinea then spreading across land borders to Sierra Leone and Liberia, by air (1 traveller) to Nigeria and USA (1 traveller), and by land to Senegal (1 traveller) and Mali (2 travellers).
The most severely affected countries, Guinea, Liberia and Sierra Leone, have very weak health systems, lack human and infrastructural resources, and have only recently emerged from long periods of conflict and instability. On August 8, the WHO Director-General declared the West Africa outbreak a Public Health Emergency of International Concern under the International Health Regulations (2005).
The virus family Filoviridae includes three genera: Cuevavirus, Marburgvirus, and Ebolavirus. There are five species that have been identified: Zaire, Bundibugyo, Sudan, Reston and Taï Forest. The first three, Bundibugyo ebolavirus, Zaire ebolavirus, and Sudan ebolavirus have been associated with large outbreaks in Africa. The virus causing the 2014 West African outbreak belongs to the Zaire species.

Transmission

It is thought that fruit bats of the Pteropodidae family are natural Ebola virus hosts. Ebola is introduced into the human population through close contact with the blood, secretions, organs or other bodily fluids of infected animals such as chimpanzees, gorillas, fruit bats, monkeys, forest antelope and porcupines found ill or dead or in the rainforest.
Ebola then spreads through human-to-human transmission via direct contact (through broken skin or mucous membranes) with the blood, secretions, organs or other bodily fluids of infected people, and with surfaces and materials (e.g. bedding, clothing) contaminated with these fluids.
Health-care workers have frequently been infected while treating patients with suspected or confirmed EVD. This has occurred through close contact with patients when infection control precautions are not strictly practiced.
Burial ceremonies in which mourners have direct contact with the body of the deceased person can also play a role in the transmission of Ebola.
People remain infectious as long as their blood contains the virus.

Sexual transmission

More surveillance data and research are needed on the risks of sexual transmission, and particularly on the prevalence of viable and transmissible virus in semen over time. In the interim, and based on present evidence, WHO recommends that:

All Ebola survivors and their sexual partners should receive counselling to ensure safe sexual practices until their semen has twice tested negative. Survivors should be provided with condoms.
Male Ebola survivors should be offered semen testing at 3 months after onset of disease, and then, for those who test positive, every month thereafter until their semen tests negative for virus twice by RT-PCR, with an interval of one week between tests.
Ebola survivors and their sexual partners should either:

abstain from all types of sex, or
observe safe sex through correct and consistent condom use until their semen has twice tested negative.

Having tested negative, survivors can safely resume normal sexual practices without fear of Ebola virus transmission.
Based on further analysis of ongoing research and consideration by the WHO Advisory Group on the Ebola Virus Disease Response, WHO recommends that male survivors of Ebola virus disease practice safe sex and hygiene for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus.
Until such time as their semen has twice tested negative for Ebola, survivors should practise good hand and personal hygiene by immediately and thoroughly washing with soap and water after any physical contact with semen, including after masturbation. During this period used condoms should be handled safely, and safely disposed of, so as to prevent contact with seminal fluids.
All survivors, their partners and families should be shown respect, dignity and compassion.

Symptoms of Ebola virus disease

The incubation period, that is, the time interval from infection with the virus to onset of symptoms is 2 to 21 days. Humans are not infectious until they develop symptoms. First symptoms are the sudden onset of fever fatigue, muscle pain, headache and sore throat. This is followed by vomiting, diarrhoea, rash, symptoms of impaired kidney and liver function, and in some cases, both internal and external bleeding (e.g. oozing from the gums, blood in the stools). Laboratory findings include low white blood cell and platelet counts and elevated liver enzymes.

Diagnosis

It can be difficult to distinguish EVD from other infectious diseases such as malaria, typhoid fever and meningitis. Confirmation that symptoms are caused by Ebola virus infection are made using the following investigations:

antibody-capture enzyme-linked immunosorbent assay (ELISA)
antigen-capture detection tests
serum neutralization test
reverse transcriptase polymerase chain reaction (RT-PCR) assay
electron microscopy
virus isolation by cell culture.

Samples from patients are an extreme biohazard risk; laboratory testing on non-inactivated samples should be conducted under maximum biological containment conditions.

Treatment and vaccines

Supportive care-rehydration with oral or intravenous fluids- and treatment of specific symptoms, improves survival. There is as yet no proven treatment available for EVD. However, a range of potential treatments including blood products, immune therapies and drug therapies are currently being evaluated. No licensed vaccines are available yet, but 2 potential vaccines are undergoing human safety testing.

Prevention and control

Good outbreak control relies on applying a package of interventions, namely case management, surveillance and contact tracing, a good laboratory service, safe burials and social mobilisation. Community engagement is key to successfully controlling outbreaks. Raising awareness of risk factors for Ebola infection and protective measures that individuals can take is an effective way to reduce human transmission. Risk reduction messaging should focus on several factors:

Reducing the risk of wildlife-to-human transmission from contact with infected fruit bats or monkeys/apes and the consumption of their raw meat. Animals should be handled with gloves and other appropriate protective clothing. Animal products (blood and meat) should be thoroughly cooked before consumption.
Reducing the risk of human-to-human transmission from direct or close contact with people with Ebola symptoms, particularly with their bodily fluids. Gloves and appropriate personal protective equipment should be worn when taking care of ill patients at home. Regular hand washing is required after visiting patients in hospital, as well as after taking care of patients at home.
Reducing the risk of possible sexual transmission, based on further analysis of ongoing research and consideration by the WHO Advisory Group on the Ebola Virus Disease Response, WHO recommends that male survivors of Ebola virus disease practice safe sex and hygiene for 12 months from onset of symptoms or until their semen tests negative twice for Ebola virus. Contact with body fluids should be avoided and washing with soap and water is recommended. WHO does not recommend isolation of male or female convalescent patients whose blood has been tested negative for Ebola virus.
Outbreak containment measures, including prompt and safe burial of the dead, identifying people who may have been in contact with someone infected with Ebola and monitoring their health for 21 days, the importance of separating the healthy from the sick to prevent further spread, and the importance of good hygiene and maintaining a clean environment.

Controlling infection in health-care settings:

Health-care workers should always take standard precautions when caring for patients, regardless of their presumed diagnosis. These include basic hand hygiene, respiratory hygiene, use of personal protective equipment (to block splashes or other contact with infected materials), safe injection practices and safe burial practices.
Health-care workers caring for patients with suspected or confirmed Ebola virus should apply extra infection control measures to prevent contact with the patient’s blood and body fluids and contaminated surfaces or materials such as clothing and bedding. When in close contact (within 1 metre) of patients with EBV, health-care workers should wear face protection (a face shield or a medical mask and goggles), a clean, non-sterile long-sleeved gown, and gloves (sterile gloves for some procedures).
Laboratory workers are also at risk. Samples taken from humans and animals for investigation of Ebola infection should be handled by trained staff and processed in suitably equipped laboratories.

Cancer

2016-02-20T09:55:00.000-08:00

Cancer, also known as a malignant tumor or malignant neoplasm, is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body.[1][2] Not all tumors are cancerous; benign tumors do not spread to other parts of the body.[2] Possible signs and symptoms include: a new lump, abnormal bleeding, a prolonged cough, unexplained weight loss, and a change in bowel movements among others.[3] While these symptoms may indicate cancer, they may also occur due to other issues.[3] There are over 100 different known cancers that affect humans.[2]

Tobacco use is the cause of about 22% of cancer deaths.[1] Another 10% is due to obesity, a poor diet, lack of physical activity, and consumption of alcohol.[1][4] Other factors include certain infections, exposure to ionizing radiation, and environmental pollutants.[5] In the developing world nearly 20% of cancers are due to infections such as hepatitis B, hepatitis C, and human papillomavirus (HPV).[1] These factors act, at least partly, by changing the genes of a cell.[6] Typically many such genetic changes are required before cancer develops.[6] Approximately 5–10% of cancers are due to genetic defects inherited from a person's parents.[7] Cancer can be detected by certain signs and symptoms or screening tests.[1] It is then typically further investigated by medical imaging and confirmed by biopsy.[8]

Many cancers can be prevented by not smoking, maintaining a healthy weight, not drinking too much alcohol, eating plenty of vegetables, fruits and whole grains, being vaccinated against certain infectious diseases, not eating too much processed and red meat, and avoiding too much exposure to sunlight.[9][10] Early detection through screening is useful for cervical and colorectal cancer.[11] The benefits of screening in breast cancer are controversial.[11][12] Cancer is often treated with some combination of radiation therapy, surgery, chemotherapy, and targeted therapy.[1][13] Pain and symptom management are an important part of care. Palliative care is particularly important in those with advanced disease.[1] The chance of survival depends on the type of cancer and extent of disease at the start of treatment.[6] In children under 15 at diagnosis the five-year survival rate in the developed world is on average 80%.[14] For cancer in the United States the average five-year survival rate is 66%.[15]

In 2012 about 14.1 million new cases of cancer occurred globally (not including skin cancer other than melanoma).[6] It caused about 8.2 million deaths or 14.6% of all human deaths.[6][16] The most common types of cancer in males are lung cancer, prostate cancer, colorectal cancer, and stomach cancer, and in females, the most common types are breast cancer, colorectal cancer, lung cancer, and cervical cancer.[6] If skin cancer other than melanoma were included in total new cancers each year it would account for around 40% of cases.[17][18] In children, acute lymphoblastic leukaemia and brain tumors are most common except in Africa where non-Hodgkin lymphoma occurs more often.[14] In 2012, about 165,000 children under 15 years of age were diagnosed with cancer. The risk of cancer increases significantly with age and many cancers occur more commonly in developed countries.[6] Rates are increasing as more people live to an old age and as lifestyle changes occur in the developing world.[19] The financial costs of cancer have been estimated at $1.16 trillion US dollars per year as of 2010.[20]

Definitions

Cancers are a large family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body.[1][2] They form a subset of neoplasms. A neoplasm or tumor is a group of cells that have undergone unregulated growth, and will often form a mass or lump, but may be distributed diffusely.[21][22]

All tumor cells show the six hallmarks of cancer. These are characteristics that the cancer cells need to produce a malignant tumor. They include:[23]

    Cell growth and division without the proper signals to do so
    Continuous growth and division even when there are signals telling them to stop
    Avoidance of programmed cell death
    Limitless number of cell divisions
    Promoting blood vessel construction
    Invasion of tissue and formation of metastases[24]

The progression from normal cells to cells that can form a detectable mass to outright cancer involves multiple steps known as malignant progression.[24][25]

Signs and symptoms

Symptoms of cancer metastasis depend on the location of the tumor.

When cancer begins, it invariably produces no symptoms. Signs and symptoms only appear as the mass continues to grow or ulcerates. The findings that result depend on the type and location of the cancer. Few symptoms are specific, with many of them also frequently occurring in individuals who have other conditions. Cancer is the new "great imitator". Thus, it is not uncommon for people diagnosed with cancer to have been treated for other diseases, which were assumed to be causing their symptoms.[26]

Local effects

Local symptoms may occur due to the mass of the tumor or its ulceration. For example, mass effects from lung cancer can cause blockage of the bronchus resulting in cough or pneumonia; esophageal cancer can cause narrowing of the esophagus, making it difficult or painful to swallow; and colorectal cancer may lead to narrowing or blockages in the bowel, resulting in changes in bowel habits. Masses in breasts or testicles may be easily felt. Ulceration can cause bleeding that, if it occurs in the lung, will lead to coughing up blood, in the bowels to anemia or rectal bleeding, in the bladder to blood in the urine, and in the uterus to vaginal bleeding. Although localized pain may occur in advanced cancer, the initial swelling is usually painless. Some cancers can cause a buildup of fluid within the chest or abdomen.[26]

Systemic symptoms

General symptoms occur due to distant effects of the cancer that are not related to direct or metastatic spread. These may include: unintentional weight loss, fever, being excessively tired, and changes to the skin.[27] Hodgkin disease, leukemias, and cancers of the liver or kidney can cause a persistent fever of unknown origin.[26]

Some cancers may cause specific groups of systemic symptoms, termed paraneoplastic phenomena. Examples include the appearance of myasthenia gravis in thymoma and clubbing in lung cancer.[26]

Metastasis

Cancer can spread from its original site by local spread, lymphatic spread to regional lymph nodes or by blood (haematogenous spread) to distant sites, known as metastasis. When cancer spreads by a haematogenous route, it usually spreads all over the body. However, cancer 'seeds' grow in certain selected site only ('soil') as hypothesized in the soil and seed hypothesis of cancer metastasis. The symptoms of metastatic cancers depend on the location of the tumor, and can include enlarged lymph nodes (which can be felt or sometimes seen under the skin and are typically hard), enlarged liver or enlarged spleen, which can be felt in the abdomen, pain or fracture of affected bones, and neurological symptoms.[26]

Causes

The great majority of cancers, some 90–95% of cases, are due to environmental factors. The remaining 5–10% are due to inherited genetics.[5] Environmental, as used by cancer researchers, means any cause that is not inherited genetically, such as lifestyle, economic and behavioral factors, and not merely pollution.[28] Common environmental factors that contribute to cancer death include tobacco (25–30%), diet and obesity (30–35%), infections (15–20%), radiation (both ionizing and non-ionizing, up to 10%), stress, lack of physical activity, and environmental pollutants.[5]

It is nearly impossible to prove what caused a cancer in any individual, because most cancers have multiple possible causes. For example, if a person who uses tobacco heavily develops lung cancer, then it was probably caused by the tobacco use, but since everyone has a small chance of developing lung cancer as a result of air pollution or radiation, then there is a small chance that the cancer developed because of air pollution or radiation. Excepting the rare transmissions that occur with pregnancies and only a marginal few organ donors, cancer is generally not a transmissible disease.[29]

Chemicals

The incidence of lung cancer is highly correlated with smoking.

Exposure to particular substances have been linked to specific types of cancer. These substances are called carcinogens. Tobacco smoking, for example, causes 90% of lung cancer.[30] It also causes cancer in the larynx, head, neck, stomach, bladder, kidney, esophagus and pancreas.[31] Tobacco smoke contains over fifty known carcinogens, including nitrosamines and polycyclic aromatic hydrocarbons.[32] Tobacco is responsible for about one in three of all cancer deaths in the developed world,[33] and about one in five worldwide.[32] Lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking rates since the 1950s followed by decreases in lung cancer death rates in men since 1990.[34][35]

In Western Europe, 10% of cancers in males and 3% of all cancers in females are attributed to alcohol exposure, especially cancer of the liver and of the digestive tract.[36] Cancer related to substance exposures at work is believed to represent between 2–20% of all cases.[37] Every year, at least 200,000 people die worldwide from cancer related to their workplaces.[38] Millions of workers run the risk of developing cancers such as lung cancer and mesothelioma from inhaling tobacco smoke or asbestos fibers on the job, or leukemia from exposure to benzene at their workplaces.[38]

Diet and exercise

Diet, physical inactivity, and obesity are related to up to 30–35% of cancer deaths.[5][39] In the United States excess body weight is associated with the development of many types of cancer and is a factor in 14–20% of all cancer deaths.[39] Correspondingly, a UK study including data on over 5 million people showed higher body mass index to be related to at least 10 types of cancer, and responsible for around 12,000 cases each year in that country.[40] Physical inactivity is believed to contribute to cancer risk, not only through its effect on body weight but also through negative effects on the immune system and endocrine system.[39] More than half of the effect from diet is due to overnutrition (eating too much), rather than from eating too few vegetables or other healthful foods.

Some specific foods are linked to specific cancers. A high-salt diet is linked to gastric cancer.[41] Aflatoxin B1, a frequent food contaminate, causes liver cancer.[41] Betel nut chewing causes oral cancer.[41] The differences in dietary practices may partly explain differences in cancer incidence in different countries. For example, gastric cancer is more common in Japan due to its high-salt diet[42] and colon cancer is more common in the United States. Immigrants develop the risk of their new country, often within one generation, suggesting a substantial link between diet and cancer.[43]

Infection

Worldwide approximately 18% of cancer deaths are related to infectious diseases.[5] This proportion varies in different regions of the world from a high of 25% in Africa to less than 10% in the developed world.[5] Viruses are the usual infectious agents that cause cancer but cancer bacteria and parasites may also have an effect.

A virus that can cause cancer is called an oncovirus. These include human papillomavirus (cervical carcinoma), Epstein–Barr virus (B-cell lymphoproliferative disease and nasopharyngeal carcinoma), Kaposi's sarcoma herpesvirus (Kaposi's sarcoma and primary effusion lymphomas), hepatitis B and hepatitis C viruses (hepatocellular carcinoma), and human T-cell leukemia virus-1 (T-cell leukemias). Bacterial infection may also increase the risk of cancer, as seen in Helicobacter pylori-induced gastric carcinoma.[44] Parasitic infections strongly associated with cancer include Schistosoma haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis viverrini and Clonorchis sinensis (cholangiocarcinoma).[45]

Radiation

Up to 10% of invasive cancers are related to radiation exposure, including both ionizing radiation and non-ionizing ultraviolet radiation.[5] Additionally, the vast majority of non-invasive cancers are non-melanoma skin cancers caused by non-ionizing ultraviolet radiation, mostly from sunlight. Sources of ionizing radiation include medical imaging and radon gas.

Ionizing radiation is not a particularly strong mutagen.[46] Residential exposure to radon gas, for example, has similar cancer risks as passive smoking.[46] Radiation is a more potent source of cancer when it is combined with other cancer-causing agents, such as radon gas exposure plus smoking tobacco.[46] Radiation can cause cancer in most parts of the body, in all animals, and at any age. Children and adolescents are twice as likely to develop radiation-induced leukemia as adults; radiation exposure before birth has ten times the effect.[46]

Medical use of ionizing radiation is a small but growing source of radiation-induced cancers. Ionizing radiation may be used to treat other cancers, but this may, in some cases, induce a second form of cancer.[46] It is also used in some kinds of medical imaging.[47]

Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.[48] Clear evidence establishes ultraviolet radiation, especially the non-ionizing medium wave UVB, as the cause of most non-melanoma skin cancers, which are the most common forms of cancer in the world.[48]

Non-ionizing radio frequency radiation from mobile phones, electric power transmission, and other similar sources have been described as a possible carcinogen by the World Health Organization's International Agency for Research on Cancer.[49] However, studies have not found a consistent link between cell phone radiation and cancer risk.[50]

Heredity

The vast majority of cancers are non-hereditary ("sporadic cancers"). Hereditary cancers are primarily caused by an inherited genetic defect. Less than 0.3% of the population are carriers of a genetic mutation that has a large effect on cancer risk and these cause less than 3–10% of all cancer.[51] Some of these syndromes include: certain inherited mutations in the genes BRCA1 and BRCA2 with a more than 75% risk of breast cancer and ovarian cancer,[51] and hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), which is present in about 3% of people with colorectal cancer,[52] among others.

Physical agents

Some substances cause cancer primarily through their physical, rather than chemical, effects on cells.[53] A prominent example of this is prolonged exposure to asbestos, naturally occurring mineral fibers that are a major cause of mesothelioma, which is a cancer of the serous membrane, usually the serous membrane surrounding the lungs.[53] Other substances in this category, including both naturally occurring and synthetic asbestos-like fibers, such as wollastonite, attapulgite, glass wool, and rock wool, are believed to have similar effects.[53] Non-fibrous particulate materials that cause cancer include powdered metallic cobalt and nickel, and crystalline silica (quartz, cristobalite, and tridymite).[53] Usually, physical carcinogens must get inside the body (such as through inhaling tiny pieces) and require years of exposure to develop cancer.[53]

Physical trauma resulting in cancer is relatively rare.[54] Claims that breaking bones resulted in bone cancer, for example, have never been proven.[54] Similarly, physical trauma is not accepted as a cause for cervical cancer, breast cancer, or brain cancer.[54] One accepted source is frequent, long-term application of hot objects to the body. It is possible that repeated burns on the same part of the body, such as those produced by kanger and kairo heaters (charcoal hand warmers), may produce skin cancer, especially if carcinogenic chemicals are also present.[54] Frequently drinking scalding hot tea may produce esophageal cancer.[54] Generally, it is believed that the cancer arises, or a pre-existing cancer is encouraged, during the process of repairing the trauma, rather than the cancer being caused directly by the trauma.[54] However, repeated injuries to the same tissues might promote excessive cell proliferation, which could then increase the odds of a cancerous mutation.

It is controversial whether chronic inflammation can directly cause mutation.[54][55] It is recognized, however, that inflammation can contribute to proliferation, survival, angiogenesis and migration of cancer cells by influencing the microenvironment around tumors.[56][57] Furthermore, oncogenes are known to build up an inflammatory pro-tumorigenic microenvironment.[58]

Hormones

Some hormones play a role in the development of cancer by promoting cell proliferation.[59] Insulin-like growth factors and their binding proteins play a key role in cancer cell proliferation, differentiation and apoptosis, suggesting possible involvement in carcinogenesis.[60]

Hormones are important agents in sex-related cancers, such as cancer of the breast, endometrium, prostate, ovary, and testis, and also of thyroid cancer and bone cancer.[59] For example, the daughters of women who have breast cancer have significantly higher levels of estrogen and progesterone than the daughters of women without breast cancer. These higher hormone levels may explain why these women have higher risk of breast cancer, even in the absence of a breast-cancer gene.[59] Similarly, men of African ancestry have significantly higher levels of testosterone than men of European ancestry, and have a correspondingly much higher level of prostate cancer.[59] Men of Asian ancestry, with the lowest levels of testosterone-activating androstanediol glucuronide, have the lowest levels of prostate cancer.[59]

Other factors are also relevant: obese people have higher levels of some hormones associated with cancer and a higher rate of those cancers.[59] Women who take hormone replacement therapy have a higher risk of developing cancers associated with those hormones.[59] On the other hand, people who exercise far more than average have lower levels of these hormones, and lower risk of cancer.[59] Osteosarcoma may be promoted by growth hormones.[59] Some treatments and prevention approaches leverage this cause by artificially reducing hormone levels, and thus discouraging hormone-sensitive cancers.[59]

Pathophysiology

Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.

Genetics

Cancer is fundamentally a disease of tissue growth regulation failure. In order for a normal cell to transform into a cancer cell, the genes that regulate cell growth and differentiation must be altered.[61]

The affected genes are divided into two broad categories. Oncogenes are genes that promote cell growth and reproduction. Tumor suppressor genes are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.[62]

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, leading to the expression of viral oncogenes in the affected cell and its descendants.

Replication of the enormous amount of data contained within the DNA of living cells will probabilistically result in some errors (mutations). Complex error correction and prevention is built into the process, and safeguards the cell against cancer. If significant error occurs, the damaged cell can "self-destruct" through programmed cell death, termed apoptosis. If the error control processes fail, then the mutations will survive and be passed along to daughter cells.

Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called carcinogens, repeated physical injury, heat, ionising radiation, or hypoxia.[63]

The errors that cause cancer are self-amplifying and compounding, for example:

    A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
    A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
    A further mutation may cause loss of a tumor suppressor gene, disrupting the apoptosis signalling pathway and resulting in the cell becoming immortal.
    A further mutation in signaling machinery of the cell might send error-causing signals to nearby cells.

The transformation of normal cell into cancer is akin to a chain reaction caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape the controls that limit normal tissue growth. This rebellion-like scenario becomes an undesirable survival of the fittest, where the driving forces of evolution work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed clonal evolution, drives progression towards more invasive stages.[64] Clonal evolution leads to intra-tumour heterogeneity that complicates designing effective treatment strategies.

Characteristic abilities developed by cancers are divided into a number of categories. Six categories were originally proposed, in a 2000 article called "The Hallmarks of Cancer" by Douglas Hanahan and Robert Weinberg: evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, and metastasis. Based on further work, the same authors added two more categories in 2011: reprogramming of energy metabolism and evasion of immune destruction.[24][25]

Epigenetics

The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis

Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumor-suppressor genes and oncogenes, and chromosomal abnormalities. However, it has become apparent that cancer is also driven by epigenetic alterations.[65]

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification[66] and changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1).[67] Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions, last for multiple generations, and can be considered to be epimutations (equivalent to mutations).

Epigenetic alterations occur frequently in cancers. As an example, Schnekenburger and Diederich[68] listed protein coding genes that were frequently altered in their methylation in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers.

While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[69][70][71][72]

Reduced expression of DNA repair genes causes deficient DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in progression to cancer.) When DNA repair is deficient DNA damages remain in cells at a higher than usual level (5th level from the top in figure), and these excess damages cause increased frequencies of mutation and/or epimutation (6th level from top of figure). Mutation rates increase substantially in cells defective in DNA mismatch repair[73][74] or in homologous recombinational repair (HRR).[75] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[76]

Higher levels of DNA damage not only cause increased mutation (right side of figure), but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[77][78]

Deficient expression of DNA repair proteins due to an inherited mutation can cause an increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[79] Germ line DNA repair mutations are noted in a box on the left side of the figure, with an arrow indicating their contribution to DNA repair deficiency. However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[80]

In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level from the top. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. In some cases, DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, there are frequent epigenetic alterations of the DNA sequences coding for small RNAs called microRNAs (or miRNAs). MiRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression.

Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see Field defects in progression to cancer). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four may be "driver" mutations, and the remaining ones may be "passenger" mutations.[81]

As pointed out above under genetic alterations, cancer is caused by failure to regulate tissue growth, when the genes that regulate cell growth and differentiation are altered. It has become clear that these alterations are caused by both DNA sequence mutation in oncogenes and tumor suppressor genes as well as by epigenetic alterations. The epigenetic deficiencies in expression of DNA repair genes, in particular, likely cause an increased frequency of mutations, some of which then occur in oncogenes and tumor suppressor genes.

Metastasis

Metastasis is the spread of cancer to other locations in the body. The new tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize.[82] Most cancer deaths are due to cancer that has spread from its primary site to other organs (metastasized).[83]

Metastasis is very common in the late stages of cancer, and it can occur via the blood or the lymphatic system or both. The typical steps in metastasis are local invasion, intravasation into the blood or lymph, circulation through the body, extravasation into the new tissue, proliferation, and angiogenesis. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the lungs, liver, brain, and the bones.[82]

Diagnosis

Chest x-ray showing lung cancer in the left lung

Most cancers are initially recognized either because of the appearance of signs or symptoms or through screening. Neither of these lead to a definitive diagnosis, which requires the examination of a tissue sample by a pathologist. People with suspected cancer are investigated with medical tests. These commonly include blood tests, X-rays, CT scans and endoscopy.

Most people are distressed to learn that they have cancer. They may become extremely anxious and depressed. The risk of suicide in people with cancer is approximately double the normal risk.[84]

Classification

Cancers are classified by the type of cell that the tumor cells resemble and is therefore presumed to be the origin of the tumor. These types include:

    Carcinoma: Cancers derived from epithelial cells. This group includes many of the most common cancers, particularly in the aged, and include nearly all those developing in the breast, prostate, lung, pancreas, and colon.

Sarcoma: Cancers arising from connective tissue (i.e. bone, cartilage, fat, nerve), each of which develops from cells originating in mesenchymal cells outside the bone marrow.

Lymphoma and leukemia: These two classes of cancer arise from hematopoietic (blood-forming) cells that leave the marrow and tend to mature in the lymph nodes and blood, respectively. Leukemia is the most common type of cancer in children accounting for about 30%.[85]

Germ cell tumor: Cancers derived from pluripotent cells, most often presenting in the testicle or the ovary (seminoma and dysgerminoma, respectively).

Blastoma: Cancers derived from immature "precursor" cells or embryonic tissue. Blastomas are more common in children than in older adults.

Cancers are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ or tissue of origin as the root. For example, cancers of the liver parenchyma arising from malignant epithelial cells is called hepatocarcinoma, while a malignancy arising from primitive liver precursor cells is called a hepatoblastoma, and a cancer arising from fat cells is called a liposarcoma. For some common cancers, the English organ name is used. For example, the most common type of breast cancer is called ductal carcinoma of the breast. Here, the adjective ductal refers to the appearance of the cancer under the microscope, which suggests that it has originated in the milk ducts.

Benign tumors (which are not cancers) are named using -oma as a suffix with the organ name as the root. For example, a benign tumor of smooth muscle cells is called a leiomyoma (the common name of this frequently occurring benign tumor in the uterus is fibroid). Confusingly, some types of cancer use the -noma suffix, examples including melanoma and seminoma.

Some types of cancer are named for the size and shape of the cells under a microscope, such as giant cell carcinoma, spindle cell carcinoma, and small-cell carcinoma.

Pathology

The tissue diagnosis given by the pathologist indicates the type of cell that is proliferating, its histological grade, genetic abnormalities, and other features of the tumor. Together, this information is useful to evaluate the prognosis of the patient and to choose the best treatment. Cytogenetics and immunohistochemistry are other types of testing that the pathologist may perform on the tissue specimen. These tests may provide information about the molecular changes (such as mutations, fusion genes, and numerical chromosome changes) that have happened in the cancer cells, and may thus also indicate the future behavior of the cancer (prognosis) and best treatment.

Prevention

Cancer prevention is defined as active measures to decrease the risk of cancer.[86] The vast majority of cancer cases are due to environmental risk factors, and many, but not all, of these environmental factors are controllable lifestyle choices. Thus, cancer is considered a largely preventable disease.[87] Between 70% and 90% of common cancers are due to environmental factors and therefore possibly preventable.[88]

Greater than 30% of cancer deaths could be prevented by avoiding risk factors including: tobacco, overweight / obesity, an insufficient diet, physical inactivity, alcohol, sexually transmitted infections, and air pollution.[89] Not all environmental causes are controllable, such as naturally occurring background radiation, and other cases of cancer are caused through hereditary genetic disorders, and thus it is not possible to prevent all cases of cancer.

Dietary

While many dietary recommendations have been proposed to reduce the risk of cancer, the evidence to support them is not definitive.[9][90] The primary dietary factors that increase risk are obesity and alcohol consumption; with a diet low in fruits and vegetables and high in red meat being implicated but not confirmed.[91][92] A 2014 meta-analysis did not find a relationship between fruits and vegetables and cancer.[93] Consumption of coffee is associated with a reduced risk of liver cancer.[94] Studies have linked excessive consumption of red or processed meat to an increased risk of breast cancer, colon cancer, and pancreatic cancer, a phenomenon that could be due to the presence of carcinogens in meats cooked at high temperatures.[95][96] This was confirmed in 2015 by the IARC of the World Health Organization, which determined that eating processed meat (e.g., bacon, ham, hot dogs, sausages) and, to a lesser degree, red meat was linked to some cancers.[97][98]

Dietary recommendations for cancer prevention typically include an emphasis on vegetables, fruit, whole grains, and fish, and an avoidance of processed and red meat (beef, pork, lamb), animal fats, and refined carbohydrates.[9][90]

Medication

The concept that medications can be used to prevent cancer is attractive, and evidence supports their use in a few defined circumstances.[99] In the general population, NSAIDs reduce the risk of colorectal cancer, however due to the cardiovascular and gastrointestinal side effects they cause overall harm when used for prevention.[100] Aspirin has been found to reduce the risk of death from cancer by about 7%.[101] COX-2 inhibitor may decrease the rate of polyp formation in people with familial adenomatous polyposis, however it is associated with the same adverse effects as NSAIDs.[102] Daily use of tamoxifen or raloxifene has been demonstrated to reduce the risk of developing breast cancer in high-risk women.[103] The benefit versus harm for 5-alpha-reductase inhibitor such as finasteride is not clear.[104]

Vitamins have not been found to be effective at preventing cancer,[105] although low blood levels of vitamin D are correlated with increased cancer risk.[106][107] Whether this relationship is causal and vitamin D supplementation is protective is not determined.[108] Beta-Carotene supplementation has been found to increase lung cancer rates in those who are high risk.[109] Folic acid supplementation has not been found effective in preventing colon cancer and may increase colon polyps.[110] It is unclear if selenium supplementation has an effect.[111]

Vaccination

Vaccines have been developed that prevent infection by some carcinogenic viruses.[112] Human papillomavirus vaccine (Gardasil and Cervarix) decreases the risk of developing cervical cancer.[112] The hepatitis B vaccine prevents infection with hepatitis B virus and thus decreases the risk of liver cancer.[112] The administration of human papillomavirus and hepatitis B vaccinations is recommended when resources allow.[113]

Screening

Unlike diagnosis efforts prompted by symptoms and medical signs, cancer screening involves efforts to detect cancer after it has formed, but before any noticeable symptoms appear.[114] This may involve physical examination, blood or urine tests, or medical imaging.[114]

Cancer screening is currently not possible for many types of cancers, and even when tests are available, they may not be recommended for everyone. Universal screening or mass screening involves screening everyone.[115] Selective screening identifies people who are known to be at higher risk of developing cancer, such as people with a family history of cancer.[115] Several factors are considered to determine whether the benefits of screening outweigh the risks and the costs of screening.[114] These factors include:

    Possible harms from the screening test: for example, X-ray images involve exposure to potentially harmful ionizing radiation.
    The likelihood of the test correctly identifying cancer.
    The likelihood of cancer being present: Screening is not normally useful for rare cancers.
    Possible harms from follow-up procedures.
    Whether suitable treatment is available.
    Whether early detection improves treatment outcomes.
    Whether the cancer will ever need treatment.
    Whether the test is acceptable to the people: If a screening test is too burdensome (for example, being extremely painful), then people will refuse to participate.[115]
    Cost of the test.

Recommendations

The U.S. Preventive Services Task Force (USPSTF) strongly recommends cervical cancer screening in women who are sexually active and have a cervix at least until the age of 65.[116] They recommend that Americans be screened for colorectal cancer via fecal occult blood testing, sigmoidoscopy, or colonoscopy starting at age 50 until age 75.[117] There is insufficient evidence to recommend for or against screening for skin cancer,[118] oral cancer,[119] lung cancer,[120] or prostate cancer in men under 75.[121] Routine screening is not recommended for bladder cancer,[122] testicular cancer,[123] ovarian cancer,[124] pancreatic cancer,[125] or prostate cancer.[126]

The USPSTF recommends mammography for breast cancer screening every two years for those 50–74 years old; however, they do not recommend either breast self-examination or clinical breast examination.[127] A 2011 Cochrane review came to slightly different conclusions with respect to breast cancer screening stating that routine mammography may do more harm than good.[128]

Japan screens for gastric cancer using photofluorography due to the high incidence there.[19]
Genetic testing
Gene     Cancer types
BRCA1, BRCA2     Breast, ovarian, pancreatic
HNPCC, MLH1, MSH2, MSH6, PMS1, PMS2     Colon, uterine, small bowel, stomach, urinary tract

Genetic testing for individuals at high-risk of certain cancers is recommended.[113][129] Carriers of these mutations may then undergo enhanced surveillance, chemoprevention, or preventative surgery to reduce their subsequent risk.[129]

Management

Many treatment options for cancer exist, with the primary ones including surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy and palliative care. Which treatments are used depends on the type, location, and grade of the cancer as well as the person's health and wishes. The treatment intent may be curative or not curative.
Chemotherapy

Chemotherapy is the treatment of cancer with one or more cytotoxic anti-neoplastic drugs (chemotherapeutic agents) as part of a standardized regimen. The term encompasses any of a large variety of different anticancer drugs, which are divided into broad categories such as alkylating agents and antimetabolites.[130] Traditional chemotherapeutic agents act by killing cells that divide rapidly, one of the main properties of most cancer cells.

Targeted therapy is a form of chemotherapy that targets specific molecular differences between cancer and normal cells. The first targeted therapies to be developed blocked the estrogen receptor molecule, inhibiting the growth of breast cancer. Another common example is the class of Bcr-Abl inhibitors, which are used to treat chronic myelogenous leukemia (CML).[131] Currently, there are targeted therapies for breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma and other cancers.[132]

The efficacy of chemotherapy depends on the type of cancer and the stage. In combination with surgery, chemotherapy has proven useful in a number of different cancer types including: breast cancer, colorectal cancer, pancreatic cancer, osteogenic sarcoma, testicular cancer, ovarian cancer, and certain lung cancers.[133] The overall effectiveness ranges from being curative for some cancers, such as some leukemias,[134][135] to being ineffective, such as in some brain tumors,[136] to being needless in others, like most non-melanoma skin cancers.[137] The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Even when it is impossible for chemotherapy to provide a permanent cure, chemotherapy may be useful to reduce symptoms like pain or to reduce the size of an inoperable tumor in the hope that surgery will be possible in the future.

Radiation

Radiation therapy involves the use of ionizing radiation in an attempt to either cure or improve the symptoms of cancer. It works by damaging the DNA of cancerous tissue leading to cellular death. To spare normal tissues (such as skin or organs, which radiation must pass through to treat the tumor), shaped radiation beams are aimed from several angles of exposure to intersect at the tumor, providing a much larger absorbed dose there than in the surrounding, healthy tissue. As with chemotherapy, different cancers respond differently to radiation therapy.[138][139][140]

Radiation therapy is used in about half of all cases and the radiation can be from either internal sources in the form of brachytherapy or external radiation sources. The radiation is most commonly low energy x-rays for treating skin cancers while higher energy x-ray beams are used in the treatment of cancers within the body.[141] Radiation is typically used in addition to surgery and or chemotherapy but for certain types of cancer, such as early head and neck cancer, may be used alone.[142] For painful bone metastasis, it has been found to be effective in about 70% of people.[142]

Surgery

Surgery is the primary method of treatment of most isolated solid cancers and may play a role in palliation and prolongation of survival. It is typically an important part of making the definitive diagnosis and staging the tumor as biopsies are usually required. In localized cancer surgery typically attempts to remove the entire mass along with, in certain cases, the lymph nodes in the area. For some types of cancer this is all that is needed to eliminate the cancer.[133]

Palliative care

Palliative care refers to treatment that attempts to make the person feel better and may or may not be combined with an attempt to treat the cancer. Palliative care includes action to reduce the physical, emotional, spiritual, and psycho-social distress experienced by people with cancer. Unlike treatment that is aimed at directly killing cancer cells, the primary goal of palliative care is to improve the person's quality of life.

People at all stages of cancer treatment should have some kind of palliative care to provide comfort. In some cases, medical specialty professional organizations recommend that people and physicians respond to cancer only with palliative care and not with cure-directed therapy.[143] This includes:[144]

    people with low performance status, corresponding with limited ability to care for themselves[143]
    people who received no benefit from prior evidence-based treatments[143]
    people who are not eligible to participate in any appropriate clinical trial[143]
    people for whom the physician sees no strong evidence that treatment would be effective[143]

Palliative care is often confused with hospice and therefore only involved when people approach end of life. Like hospice care, palliative care attempts to help the person cope with the immediate needs and to increase the person's comfort. Unlike hospice care, palliative care does not require people to stop treatment aimed at prolonging their lives or curing the cancer.

Multiple national medical guidelines recommend early palliative care for people whose cancer has produced distressing symptoms (pain, shortness of breath, fatigue, nausea) or who need help coping with their illness. In people who have metastatic disease when first diagnosed, oncologists should consider a palliative care consult immediately. Additionally, an oncologist should consider a palliative care consult in any person they feel has less than 12 months of life even if continuing aggressive treatment.[145][146][147]

Immunotherapy

A variety of therapies using immunotherapy, stimulating or helping the immune system to fight cancer, have come into use since 1997, and this continues to be an area of very active research.[148]
Alternative medicine

Complementary and alternative cancer treatments are a diverse group of health care systems, practices, and products that are not part of conventional medicine.[149] "Complementary medicine" refers to methods and substances used along with conventional medicine, while "alternative medicine" refers to compounds used instead of conventional medicine.[150] Most complementary and alternative medicines for cancer have not been rigorously studied or tested. Some alternative treatments have been investigated and shown to be ineffective but still continue to be marketed and promoted. Cancer researcher Andrew J. Vickers has stated: "The label 'unproven' is inappropriate for such therapies; it is time to assert that many alternative cancer therapies have been 'disproven'."[151]

Prognosis

Cancer has a reputation as a deadly disease. Taken as a whole, about half of people receiving treatment for invasive cancer (excluding carcinoma in situ and non-melanoma skin cancers) die from cancer or its treatment.[19] Survival is worse in the developing world,[19] partly because the types of cancer that are most common there are at present harder to treat than those associated with the lifestyle of developed countries.[152] However, the survival rates vary dramatically by type of cancer, and by the stage at which it is diagnosed, with the range running from the great majority of people surviving to almost no one surviving as long as five years after diagnosis. Once a cancer has metastasized or spread beyond its original site, the prognosis normally becomes much worse.

Those who survive cancer are at increased risk of developing a second primary cancer at about twice the rate of those never diagnosed with cancer.[153] The increased risk is believed to be primarily due to the same risk factors that produced the first cancer, partly due to the treatment for the first cancer, and potentially related to better compliance with screening.[153]

Predicting either short-term or long-term survival is difficult and depends on many factors. The most important factors are the particular kind of cancer and the patient's age and overall health. People who are frail with many other health problems have lower survival rates than otherwise healthy people. A centenarian is unlikely to survive for five years even if the treatment is successful. People who report a higher quality of life tend to survive longer.[154] People with lower quality of life may be affected by major depressive disorder and other complications from cancer treatment and/or disease progression that both impairs their quality of life and reduces their quantity of life. Additionally, patients with worse prognoses may be depressed or report a lower quality of life directly because they correctly perceive that their condition is likely to be fatal.

People with cancer, even those who are walking on their own, have an increased risk of blood clots in veins. The use of heparin appears improve survival and decrease the risk of blood clots.[155]

Epidemiology

In 2008, approximately 12.7 million cancers were diagnosed (excluding non-melanoma skin cancers and other non-invasive cancers),[19] and in 2010 nearly 7.98 million people died.[157] Cancers as a group account for approximately 13% of all deaths each year with the most common being: lung cancer (1.4 million deaths), stomach cancer (740,000 deaths), liver cancer (700,000 deaths), colorectal cancer (610,000 deaths), and breast cancer (460,000 deaths).[158] This makes invasive cancer the leading cause of death in the developed world and the second leading cause of death in the developing world.[19] Over half of cases occur in the developing world.[19]

Deaths from cancer were 5.8 million in 1990[157] and rates have been increasing primarily due to an aging population and lifestyle changes in the developing world.[19] The most significant risk factor for developing cancer is old age.[159] Although it is possible for cancer to strike at any age, most people who are diagnosed with invasive cancer are over the age of 65.[159] According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer."[160] Some of the association between aging and cancer is attributed to immunosenescence,[161] errors accumulated in DNA over a lifetime,[162] and age-related changes in the endocrine system.[163] The effect of aging on cancer is complicated with a number of factors such as DNA damage and inflammation promoting it and a number of factors such as vascular aging and endocrine changes inhibiting it.[164]

Some slow-growing cancers are particularly common. Autopsy studies in Europe and Asia have shown that up to 36% of people have undiagnosed and apparently harmless thyroid cancer at the time of their deaths, and that 80% of men develop prostate cancer by age 80.[165][166] As these cancers did not cause the person's death, identifying them would have represented overdiagnosis rather than useful medical care.
The three most common childhood cancers are leukemia (34%), brain tumors (23%), and lymphomas (12%).[167] In the United States cancer affects about 1 in 285 children.[168] Rates of childhood cancer have increased by 0.6% per year between 1975 to 2002 in the United States[169] and by 1.1% per year between 1978 and 1997 in Europe.[167] Death from childhood cancer have decreased by half since 1975 in the United States.[168]

Hypertension

2016-02-20T06:08:00.000-08:00

Hypertension (HTN or HT), also known as high blood pressure, is a long term medical condition in which the blood pressure in the arteries is persistently elevated. Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are the maximum and minimum pressures, respectively, in the arterial system. The systolic pressure occurs when the left ventricle is most contracted; the diastolic pressure occurs when the left ventricle is most relaxed prior to the next contraction. Normal blood pressure at rest is within the range of 100–140 millimeters mercury (mmHg) systolic and 60–90 mmHg diastolic. Hypertension is present if the resting blood pressure is persistently at or above 140/90 mmHg for most adults; different numbers apply to children.[1]

Hypertension usually does not cause symptoms initially, but sustained hypertension over time is a major risk factor for hypertensive heart disease, coronary artery disease,[2] stroke, aortic aneurysm, peripheral artery disease, and chronic kidney disease.

Hypertension is classified as either primary (essential) hypertension or secondary hypertension. About 90–95% of cases are categorized as primary hypertension, defined as high blood pressure with no obvious underlying cause.[3] The remaining 5–10% of cases are categorized as secondary hypertension, defined as hypertension due to an identifiable cause, such as chronic kidney disease, narrowing of the aorta or kidney arteries, or an endocrine disorder such as excess aldosterone, cortisol, or catecholamines.

Dietary and lifestyle changes can lower blood pressure and decrease the risk of health complications, although treatment with medication is still often necessary in people for whom lifestyle changes are not enough or not effective. The treatment of moderately high arterial blood pressure (defined as >160/100 mmHg) with medications is associated with an improved life expectancy.[4] The benefits of treatment of blood pressure that is between 140/90 mmHg and 160/100 mmHg are less clear, with some reviews finding absence of a proven benefit[5] and others finding benefit.[6][7]

Signs and symptoms

Hypertension is rarely accompanied by any symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. Some with high blood pressure report headaches (particularly at the back of the head and in the morning), as well as lightheadedness, vertigo, tinnitus (buzzing or hissing in the ears), altered vision or fainting episodes.[8] These symptoms, however, might be related to associated anxiety rather than the high blood pressure itself.[9]

On physical examination, hypertension may be associated with the presence of changes in the optic fundus seen by ophthalmoscopy.[10] The severity of the changes typical of hypertensive retinopathy is graded from I–IV; grades I and II may be difficult to differentiate.[10] The severity of the retinopathy correlates roughly with the duration and/or the severity of the hypertension.[8]

Secondary hypertension

Hypertension with certain specific additional signs and symptoms may suggest secondary hypertension, i.e. hypertension due to an identifiable cause. For example, Cushing's syndrome frequently causes truncal obesity, glucose intolerance, moon face, a hump of fat behind the neck/shoulder, and purple abdominal stretch marks.[11] Hyperthyroidism frequently causes weight loss with increased appetite, fast heart rate, bulging eyes, and tremor. Renal artery stenosis (RAS) may be associated with a localized abdominal bruit to the left or right of the midline (unilateral RAS), or in both locations (bilateral RAS). Coarctation of the aorta frequently causes a decreased blood pressure in the lower extremities relative to the arms, and/or delayed or absent femoral arterial pulses. Pheochromocytoma may cause abrupt ("paroxysmal") episodes of hypertension accompanied by headache, palpitations, pale appearance, and excessive sweating.[11]

Hypertensive crisis

Severely elevated blood pressure (equal to or greater than a systolic 180 or diastolic of 110) is referred to as a hypertensive crisis. Hypertensive crisis is categorized as either hypertensive urgency or hypertensive emergency, according to the absence or presence of end organ damage, respectively.[12][13]

In hypertensive urgency, there is no evidence of end organ damage resulting from the elevated blood pressure. In these cases, oral medications are used to lower the BP gradually over 24 to 48 hours.[14]

In hypertensive emergency, there is evidence of direct damage to one or more organs.[15][16] The most affected organs include the brain, kidney, heart and lungs, producing symptoms which may include confusion, drowsiness, chest pain and breathlessness.[14] In hypertensive emergency, the blood pressure must be reduced more rapidly to stop ongoing organ damage,[14] however, there is a lack of randomised controlled trial evidence for this approach.[16]

Pregnancy

Hypertension occurs in approximately 8–10% of pregnancies.[11] Two blood pressure measurements six hours apart of greater than 140/90 mm Hg is considered diagnostic of hypertension in pregnancy.[17] High blood pressure in pregnancy can be classified as pre-existing hypertension, gestational hypertension or pre-eclampsia.[18]

Pre-eclampsia is a serious condition of the second half of pregnancy and following delivery characterised by increased blood pressure and the presence of protein in the urine.[11] It occurs in about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths globally.[11] Pre-eclampsia also doubles the risk of perinatal mortality.[11] Usually there are no symptoms in pre-eclampsia and it is detected by routine screening. When symptoms of pre-eclampsia occur the most common are headache, visual disturbance (often "flashing lights"), vomiting, pain over the stomach, and swelling. Pre-eclampsia can occasionally progress to a life-threatening condition called eclampsia, which is a hypertensive emergency and has several serious complications including vision loss, brain swelling, seizures, kidney failure, pulmonary edema, and disseminated intravascular coagulation (a blood clotting disorder).[11][19]

In contrast, gestational hypertension is defined as new-onset hypertension during pregnancy without protein in the urine.[18]

Children

Failure to thrive, seizures, irritability, lack of energy, and difficulty breathing[20] can be associated with hypertension in neonates and young infants. In older infants and children, hypertension can cause headache, unexplained irritability, fatigue, failure to thrive, blurred vision, nosebleeds, and facial paralysis.[20][21]

Causes

Primary hypertension

Hypertension results from a complex interaction of genes and environmental factors. Numerous common genetic variants with small effects on blood pressure have been identified[22] as well as some rare genetic variants with large effects on blood pressure,[23] but the genetic basis of hypertension is still poorly understood.

Blood pressure rises with aging and the risk of becoming hypertensive in later life is considerable.[24] Several environmental factors influence blood pressure. High salt intake raises the blood pressure in salt sensitive individuals; lack of exercise, obesity, stress,[9] and depression[25] can play a role in individual cases. The possible role of other factors such as caffeine consumption,[26] and vitamin D deficiency[27] are less clear. Insulin resistance, which is common in obesity and is a component of syndrome X (or the metabolic syndrome), is also thought to contribute to hypertension.[28] Events in early life, such as low birth weight, maternal smoking, and lack of breast feeding may be risk factors for adult essential hypertension, although the mechanisms linking these exposures to adult hypertension remain unclear.[29] An increased rate of high blood urea has been found in untreated people with hypertensive in comparison with people with normal blood pressure, although it is uncertain whether the former plays a causal role or is subsidiary to poor kidney function.[30]

Secondary hypertension

Secondary hypertension results from an identifiable cause. Kidney disease is the most common secondary cause of hypertension.[11] Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, hyperparathyroidism and pheochromocytoma.[11][31] Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive liquorice consumption and certain prescription medicines, herbal remedies and illegal drugs.[11][32] Arsenic exposure through drinking water has been shown to correlate with elevated blood pressure.[33][34]

Pathophysiology

In most people with established essential hypertension, increased resistance to blood flow (total peripheral resistance) accounts for the high pressure while cardiac output remains normal.[35] There is evidence that some younger people with prehypertension or 'borderline hypertension' have high cardiac output, an elevated heart rate and normal peripheral resistance, termed hyperkinetic borderline hypertension.[36] These individuals develop the typical features of established essential hypertension in later life as their cardiac output falls and peripheral resistance rises with age.[36] Whether this pattern is typical of all people who ultimately develop hypertension is disputed.[37] The increased peripheral resistance in established hypertension is mainly attributable to structural narrowing of small arteries and arterioles,[38] although a reduction in the number or density of capillaries may also contribute.[39] Whether increased active arteriolar vasoconstriction plays a role in established essential hypertension is unclear.[40] Hypertension is also associated with decreased peripheral venous compliance[41] which may increase venous return, increase cardiac preload and, ultimately, cause diastolic dysfunction.

Pulse pressure (the difference between systolic and diastolic blood pressure) is frequently increased in older people with hypertension. This can mean that systolic pressure is abnormally high, but diastolic pressure may be normal or low — a condition termed isolated systolic hypertension.[42] The high pulse pressure in elderly people with hypertension or isolated systolic hypertension is explained by increased arterial stiffness, which typically accompanies aging and may be exacerbated by high blood pressure.[43]

Many mechanisms have been proposed to account for the rise in peripheral resistance in hypertension. Most evidence implicates either disturbances in the kidneys' salt and water handling (particularly abnormalities in the intrarenal renin-angiotensin system)[44] and/or abnormalities of the sympathetic nervous system.[45] These mechanisms are not mutually exclusive and it is likely that both contribute to some extent in most cases of essential hypertension. It has also been suggested that endothelial dysfunction and vascular inflammation may also contribute to increased peripheral resistance and vascular damage in hypertension.[46][47] Interleukin 17 has garnered interest for its role in increasing the production of several other immune system chemical signals thought to be involved in hypertension such as tumor necrosis factor alpha, interleukin 1, interleukin 6, and interleukin 8.[48]

Diagnosis

Typical tests performed

System       Tests
Kidney             Microscopic urinalysis, protein in the urine, BUN and/or creatinine
Endocrine         Serum sodium, potassium, calcium, TSH
Metabolic Fasting blood glucose, HDL, LDL, and total cholesterol, triglycerides
Other               Hematocrit, electrocardiogram, and chest radiograph

Hypertension is diagnosed on the basis of a persistently high blood pressure. Traditionally, the National Institute of Clinical Excellence recommends three separate sphygmomanometer measurements at one monthly intervals.[55][56] The American Heart Association recommends at least three measurements on at least two separate health care visits.[57] Ambulatory blood pressure monitoring over 12 to 24 hours is the most accurate method to confirm the diagnosis.[58]

An exception to this is those with very high blood pressure readings especially when there is poor organ function.[56] Initial assessment of the hypertensive people should include a complete history and physical examination. With the availability of 24-hour ambulatory blood pressure monitors and home blood pressure machines, the importance of not wrongly diagnosing those who have white coat hypertension has led to a change in protocols. In the United Kingdom, current best practice is to follow up a single raised clinic reading with ambulatory measurement, or less ideally with home blood pressure monitoring over the course of 7 days.[56] The United States Preventative Services Task Force also recommends getting measurements outside of the healthcare environment.[59] Pseudohypertension in the elderly or noncompressibility artery syndrome may also require consideration. This condition is believed to be due to calcification of the arteries resulting in abnormally high blood pressure readings with a blood pressure cuff while intra arterial measurements of blood pressure are normal.[60] Orthostatic hypertension is when blood pressure increases upon standing.[61]

Once the diagnosis of hypertension has been made, healthcare providers should attempt to identify the underlying cause based on risk factors and other symptoms, if present. Secondary hypertension is more common in preadolescent children, with most cases caused by kidney disease. Primary or essential hypertension is more common in adolescents and has multiple risk factors, including obesity and a family history of hypertension.[62] Laboratory tests can also be performed to identify possible causes of secondary hypertension, and to determine whether hypertension has caused damage to the heart, eyes, and kidneys. Additional tests for diabetes and high cholesterol levels are usually performed because these conditions are additional risk factors for the development of heart disease and may require treatment.[3]

Serum creatinine is measured to assess for the presence of kidney disease, which can be either the cause or the result of hypertension. Serum creatinine alone may overestimate glomerular filtration rate and recent guidelines advocate the use of predictive equations such as the Modification of Diet in Renal Disease (MDRD) formula to estimate glomerular filtration rate (eGFR).[63] eGFR can also provide a baseline measurement of kidney function that can be used to monitor for side effects of certain antihypertensive drugs on kidney function. Additionally, testing of urine samples for protein is used as a secondary indicator of kidney disease. Electrocardiogram (EKG/ECG) testing is done to check for evidence that the heart is under strain from high blood pressure. It may also show whether there is thickening of the heart muscle (left ventricular hypertrophy) or whether the heart has experienced a prior minor disturbance such as a silent heart attack. A chest X-ray or an echocardiogram may also be performed to look for signs of heart enlargement or damage to the heart.[11]

Adults

Classification of blood pressure for adults (JNC7)

Category       systolic, mm Hg                    diastolic, mm Hg
Normal                           90–119             60–79
High normal[64]
(Prehypertension)                 120–139        80–89
Stage 1 hypertension            140–159                                90–99
Stage 2 hypertension                  160–179                                100–109
Stage 3 hypertension[65][66]
(Hypertensive emergency)           ≥180                                     ≥110
Isolated systolic hypertension       ≥140     <90

In people aged 18 years or older hypertension is defined as a systolic and/or a diastolic blood pressure measurement consistently higher than an accepted normal value (currently 139 mmHg systolic, 89 mmHg diastolic: see table—Classification (JNC7)). Lower thresholds are used (135 mmHg systolic or 85 mmHg diastolic) if measurements are derived from 24-hour ambulatory or home monitoring.[56] Recent international hypertension guidelines have also created categories below the hypertensive range to indicate a continuum of risk with higher blood pressures in the normal range. JNC7 (2003)[63] uses the term prehypertension for blood pressure in the range 120–139 mmHg systolic and/or 80–89 mmHg diastolic, while ESH-ESC Guidelines (2007)[65] and BHS IV (2004)[66] use optimal, normal and high normal categories to subdivide pressures below 140 mmHg systolic and 90 mmHg diastolic. Hypertension is also sub-classified: JNC7 distinguishes hypertension stage I, hypertension stage II, and isolated systolic hypertension. Isolated systolic hypertension refers to elevated systolic pressure with normal diastolic pressure and is common in the elderly.[63] The ESH-ESC Guidelines (2007)[65] and BHS IV (2004)[66] additionally define a third stage (stage III hypertension) for people with systolic blood pressure exceeding 179 mmHg or a diastolic pressure over 109 mmHg. Hypertension is classified as "resistant" if medications do not reduce blood pressure to normal levels.[63]

Children

Hypertension occurs in around 0.2 to 3% of newborns; however, blood pressure is not measured routinely in healthy newborns.[21] Hypertension is more common in high risk newborns. A variety of factors, such as gestational age, postconceptional age and birth weight needs to be taken into account when deciding if a blood pressure is normal in a newborn.[21]

Hypertension defined as elevated blood pressure over several visits affects 1% to 5% of children and adolescents and is associated with long term risks of ill-health.[67] Blood pressure rises with age in childhood and, in children, hypertension is defined as an average systolic or diastolic blood pressure on three or more occasions equal or higher than the 95th percentile appropriate for the sex, age and height of the child. High blood pressure must be confirmed on repeated visits however before characterizing a child as having hypertension.[67] Prehypertension in children has been defined as average systolic or diastolic blood pressure that is greater than or equal to the 90th percentile, but less than the 95th percentile.[67] In adolescents, it has been proposed that hypertension and pre-hypertension are diagnosed and classified using the same criteria as in adults.[67]

The value of routine screening for hypertension in children over the age of 3 years is debated.[68][69] In 2004 the National High Blood Pressure Education Program recommended that children aged 3 years and older have blood pressure measurement at least once at every health care visit[67] and the National Heart, Lung, and Blood Institute and American Academy of Pediatrics made a similar recommendation.[70] However, the American Academy of Family Physicians[71] support the view of the U.S. preventive Services Task Force that evidence is insufficient to determine the balance of benefits and harms of screening for hypertension in children and adolescents who do not have symptoms.[72]

Prevention

Much of the disease burden of high blood pressure is experienced by people who are not labeled as hypertensive.[66] Consequently, population strategies are required to reduce the consequences of high blood pressure and reduce the need for antihypertensive drug therapy. Lifestyle changes are recommended to lower blood pressure, before starting drug therapy. The 2004 British Hypertension Society guidelines[66] proposed the following lifestyle changes consistent with those outlined by the US National High BP Education Program in 2002[73] for the primary prevention of hypertension:

    maintain normal body weight for adults (e.g. body mass index 20–25 kg/m2)
    reduce dietary sodium intake to <100 mmol/ day (<6 g of sodium chloride or <2.4 g of sodium per day)
    engage in regular aerobic physical activity such as brisk walking (≥30 min per day, most days of the week)
    limit alcohol consumption to no more than 3 units/day in men and no more than 2 units/day in women
    consume a diet rich in fruit and vegetables (e.g. at least five portions per day);

Effective lifestyle modification may lower blood pressure as much as an individual antihypertensive drug. Combinations of two or more lifestyle modifications can achieve even better results.[66]

Management

According to one review published in 2003, reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease.[74]
Target blood pressure

Various expert groups have produced guidelines regarding how low the blood pressure target should be when a person is treated for hypertension. These groups recommend a target below the range 140-160 / 90-100 mmHg for the general population.[1][75][76][77][78] Controversy exists regarding the appropriate targets for certain subgroups, including the elderly, people with diabetes and people with kidney disease.[79]

Many expert groups recommend a slightly higher target of 150/90 mmHg for those over 80 years of age.[75][76][77] One expert group, the JNC-8, recommends the target of 150/90 mmHg for those over 60 years of age,[1] but some experts within this group disagree with this recommendation.[80] Some expert groups have also recommended slightly lower targets in those with diabetes[75] or chronic kidney disease with proteinuria,[81] but others recommend the same target as for the general population.[1][79] In 2015 a large trial suggests that among people over 50 with increased heart disease risk, aiming to reduce systolic blood pressure to 120 mmHg was associated with lower mortality but increased side effects compared to a target of 140 mmHg.[82]

Lifestyle modifications

The first line of treatment for hypertension is lifestyle changes, including dietary changes,[83] physical exercise, and weight loss. These have all been shown to significantly reduce blood pressure in people with hypertension.[84] Their potential effectiveness is similar to and at times exceeds a single medication.[64] If hypertension is high enough to justify immediate use of medications, lifestyle changes are still recommended in conjunction with medication.

Dietary changes shown to reduce blood pressure include diets with low sodium,[85] the DASH diet, vegetarian diets[86] and high potassium diets.[87]

Physical exercise regimens which are shown to reduce blood pressure include isometric resistance exercise, aerobic exercise, resistance exercise, and device-guided breathing.[88]

Stress reduction techniques such as biofeedback or transcendental meditation may be considered as an add-on to other treatments to reduce hypertension, but do not have evidence for preventing cardiovascular disease on their own.[88][89][90]

Medications

Several classes of medications, collectively referred to as antihypertensive medications, are available for treating hypertension.

First line medications for hypertension include thiazide-diuretics, calcium channel blockers, angiotensin converting enzyme inhibitors and angiotensin receptor blockers.[1] These drugs may be used alone or in combination; the latter option may serve to minimize counter-regulatory mechanisms that act to revert blood pressure values to pre-treatment levels.[1][91] The majority of people require more than one medication to control their hypertension.[84]

Resistant hypertension

Resistant hypertension is defined as hypertension that remains above goal blood pressure in spite of using, at once, three antihypertensive medications belonging to different drug classes. Low adherence to treatment is an important cause of resistant hypertension.[92] Resistant hypertension may also represent the result of chronic high activity of the autonomic nervous system; this concept is known as "neurogenic hypertension".[93]

Epidemiology

As of 2000, nearly one billion people or ~26% of the adult population of the world had hypertension.[95] It was common in both developed (333 million) and undeveloped (639 million) countries.[95] However, rates vary markedly in different regions with rates as low as 3.4% (men) and 6.8% (women) in rural India and as high as 68.9% (men) and 72.5% (women) in Poland.[96] In Europe hypertension occurs in about 30-45% of people as of 2013.[64]

In 1995 it was estimated that 43 million people in the United States had hypertension or were taking antihypertensive medication, almost 24% of the adult United States population.[97] The prevalence of hypertension in the United States is increasing and reached 29% in 2004.[98][99] As of 2006 hypertension affects 76 million US adults (34% of the population) and African American adults have among the highest rates of hypertension in the world at 44%.[100] It is more common in blacks and less in whites and Mexican Americans, rates increase with age, and is greater in the southeastern United States.[3][101] Hypertension is more common in men (though menopause tends to decrease this difference) and in those of low socioeconomic status.[3]

Children

Rates of high blood pressure in children and adolescents have increased in the last 20 years in the United States.[102] Childhood hypertension, particularly in preadolescents, is more often secondary to an underlying disorder than in adults. Kidney disease is the most common secondary cause of hypertension in children and adolescents. Nevertheless, primary or essential hypertension accounts for most cases.[103]

Outcomes

Hypertension is the most important preventable risk factor for premature death worldwide.[104] It increases the risk of ischemic heart disease[105] strokes,[11] peripheral vascular disease,[106] and other cardiovascular diseases, including heart failure, aortic aneurysms, diffuse atherosclerosis, chronic kidney disease, and pulmonary embolism.[11] Hypertension is also a risk factor for cognitive impairment and dementia.[11] Other complications include hypertensive retinopathy and hypertensive nephropathy.[63]

History

Modern understanding of the cardiovascular system began with the work of physician William Harvey (1578–1657), who described the circulation of blood in his book "De motu cordis". The English clergyman Stephen Hales made the first published measurement of blood pressure in 1733.[107][108] However hypertension as a clinical entity came into being in 1896 with the invention of the cuff-based sphygmomanometer by Scipione Riva-Rocci in 1896.[109] This allowed the measurement of blood pressure in the clinic. In 1905, Nikolai Korotkoff improved the technique by describing the Korotkoff sounds that are heard when the artery is ausculated with a stethoscope while the sphygmomanometer cuff is deflated.[108]

Identification

The symptoms similar to symptoms of patients with hypertensive crisis are discussed in medieval Persian medical texts in the chapter of "fullness disease".[110] The symptoms include headache, heaviness in the head, sluggish movements, general redness and warm to touch feel of the body, prominent, distended and tense vessels, fullness of the pulse, distension of the skin, coloured and dense urine, loss of appetite, weak eyesight, impairment of thinking, yawning, drowsiness, vascular rupture, and hemorrhagic stroke.[111] Fullness disease was presumed to be due to an excessive amount of blood within the blood vessels.

Descriptions of hypertension as a disease came among others from Thomas Young in 1808 and especially Richard Bright in 1836.[107] The first report of elevated blood pressure in a person without evidence of kidney disease was made by Frederick Akbar Mahomed (1849–1884).[112]

Treatment

Historically the treatment for what was called the "hard pulse disease" consisted in reducing the quantity of blood by bloodletting or the application of leeches.[107] This was advocated by The Yellow Emperor of China, Cornelius Celsus, Galen, and Hippocrates.[107] The therapeutic approach for the treatment of hard pulse disease included changes in lifestyle (staying away from anger and sexual intercourse) and dietary program for patients (avoiding the consumption of wine, meat, and pastries, reducing the volume of food in a meal, maintaining a low-energy diet and the dietary usage of spinach and vinegar).

In the 19th and 20th centuries, before effective pharmacological treatment for hypertension became possible, three treatment modalities were used, all with numerous side-effects: strict sodium restriction (for example the rice diet[107]), sympathectomy (surgical ablation of parts of the sympathetic nervous system), and pyrogen therapy (injection of substances that caused a fever, indirectly reducing blood pressure).[107][113]

The first chemical for hypertension, sodium thiocyanate, was used in 1900 but had many side effects and was unpopular.[107] Several other agents were developed after the Second World War, the most popular and reasonably effective of which were tetramethylammonium chloride, hexamethonium, hydralazine and reserpine (derived from the medicinal plant Rauwolfia serpentina). None of these were well tolerated. A major breakthrough was achieved with the discovery of the first well-tolerated orally available agents. The first was chlorothiazide, the first thiazide diuretic and developed from the antibiotic sulfanilamide, which became available in 1958.[107][114] Subsequently beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and renin inhibitors were developed as antihypertensive agents.[113]

Diabetes mellitus

2016-02-20T05:32:00.000-08:00

Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic diseases in which there are high blood sugar levels over a prolonged period.[2] Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications.[3] Acute complications include diabetic ketoacidosis and nonketotic hyperosmolar coma.[4] Serious long-term complications include cardiovascular disease, stroke, chronic kidney failure, foot ulcers, and damage to the eyes.[3]

Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced.[5] There are three main types of diabetes mellitus:

    Type 1 DM results from the pancreas's failure to produce enough insulin. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". The cause is unknown.[3]
    Type 2 DM begins with insulin resistance, a condition in which cells fail to respond to insulin properly.[3] As the disease progresses a lack of insulin may also develop.[6] This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes". The primary cause is excessive body weight and not enough exercise.[3]
    Gestational diabetes, is the third main form and occurs when pregnant women without a previous history of diabetes develop high blood-sugar levels.[3]

Prevention and treatment involve a healthy diet, physical exercise, maintaining a normal body weight, and avoiding use of tobacco. Control of blood pressure and maintaining proper foot care are important for people with the disease. Type 1 DM must be managed with insulin injections.[3] Type 2 DM may be treated with medications with or without insulin.[7] Insulin and some oral medications can cause low blood sugar.[8] Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 DM.[9] Gestational diabetes usually resolves after the birth of the baby.[10]

As of 2014, an estimated 387 million people have diabetes worldwide,[11] with type 2 DM making up about 90% of the cases.[12][13] This represents 8.3% of the adult population,[13] with equal rates in both women and men.[14] From 2012 to 2014, diabetes is estimated to have resulted in 1.5 to 4.9 million deaths each year.[7][11] Diabetes at least doubles a person's risk of death.[3] The number of people with diabetes is expected to rise to 592 million by 2035.[11] The global economic cost of diabetes in 2014 was estimated to be $612 billion USD.[15] In the United States, diabetes cost $245 billion in 2012.[16]

Signs and symptoms

Overview of the most significant symptoms of diabetes

The classic symptoms of untreated diabetes are weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger).[17] Symptoms may develop rapidly (weeks or months) in type 1 DM, while they usually develop much more slowly and may be subtle or absent in type 2 DM.

Several other signs and symptoms can mark the onset of diabetes, although they are not specific to the disease. In addition to the known ones above, they include blurry vision, headache, fatigue, slow healing of cuts, and itchy skin. Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.

Diabetic Emergencies

Low blood sugar is common in persons with type 1 and type 2 DM. Most cases are mild and are not considered medical emergencies. Effects can range from feelings of unease, sweating, trembling, and increased appetite in mild cases to more serious issues such as confusion, changes in behavior, seizures, unconsciousness, and (rarely) permanent brain damage or death in severe cases.[18][19] Mild cases are self-treated by eating or drinking something high in sugar. Severe cases can lead to unconsciousness and must be treated with intravenous glucose or injections with glucagon.

People (usually with type 1 DM) may also experience episodes of diabetic ketoacidosis, a metabolic disturbance characterized by nausea, vomiting and abdominal pain, the smell of acetone on the breath, deep breathing known as Kussmaul breathing, and in severe cases a decreased level of consciousness.[20]

A rare but equally severe possibility is hyperosmolar nonketotic state, which is more common in type 2 DM and is mainly the result of dehydration.[20]

Complications

All forms of diabetes increase the risk of long-term complications. These typically develop after many years (10–20), but may be the first symptom in those who have otherwise not received a diagnosis before that time.

The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease[21] and about 75% of deaths in diabetics are due to coronary artery disease.[22] Other "macrovascular" diseases are stroke, and peripheral vascular disease.

The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves.[23] Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and blindness.[23] Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplant.[23] Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes.[23] The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy causes painful muscle wasting and weakness.

There is a link between cognitive deficit and diabetes. Compared to those without diabetes, those with the disease have a 1.2 to 1.5-fold greater rate of decline in cognitive function.[24]

Causes

Diabetes mellitus is classified into four broad categories: type 1, type 2, gestational diabetes, and "other specific types".[5] The "other specific types" are a collection of a few dozen individual causes.[5] The term "diabetes", without qualification, usually refers to diabetes mellitus.

Type 1

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a T-cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin.[26] It causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these diabetes cases were in children.

"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used.[27] Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, frequently with ketosis, and sometimes with serious low blood sugar levels. Other complications include an impaired counterregulatory response to low blood sugar, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease).[27] These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.[28]

Type 1 diabetes is partly inherited, with multiple genes, including certain HLA genotypes, known to influence the risk of diabetes. In genetically susceptible people, the onset of diabetes can be triggered by one or more environmental factors, such as a viral infection or diet. There is some evidence that suggests an association between type 1 DM and Coxsackie B4 virus. Unlike type 2 DM, the onset of type 1 diabetes is unrelated to lifestyle.

Type 2

Type 2 DM is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion.[5] The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are classified separately. Type 2 DM is the most common type of diabetes mellitus.

In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, high blood sugar can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce the liver's glucose production.

Type 2 DM is due primarily to lifestyle factors and genetics.[29] A number of lifestyle factors are known to be important to the development of type 2 DM, including obesity (defined by a body mass index of greater than 30), lack of physical activity, poor diet, stress, and urbanization.[12] Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders.[5] Even those who are not obese often have a high waist–hip ratio.[5]

Dietary factors also influence the risk of developing type 2 DM. Consumption of sugar-sweetened drinks in excess is associated with an increased risk.[30][31] The type of fats in the diet is also important, with saturated fats and trans fatty acids increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk.[29] Eating lots of white rice also may increase the risk of diabetes.[32] A lack of exercise is believed to cause 7% of cases.[33]

Gestational diabetes

Gestational diabetes mellitus (GDM) resembles type 2 DM in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness. It occurs in about 2–10% of all pregnancies and may improve or disappear after delivery.[34] However, after pregnancy approximately 5–10% of women with gestational diabetes are found to have diabetes mellitus, most commonly type 2.[34] Gestational diabetes is fully treatable, but requires careful medical supervision throughout the pregnancy. Management may include dietary changes, blood glucose monitoring, and in some cases insulin may be required.

Though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother. Risks to the baby include macrosomia (high birth weight), congenital heart and central nervous system abnormalities, and skeletal muscle malformations. Increased levels of insulin in a fetus's blood may inhibit fetal surfactant production and cause respiratory distress syndrome. A high blood bilirubin level may result from red blood cell destruction. In severe cases, perinatal death may occur, most commonly as a result of poor placental perfusion due to vascular impairment. Labor induction may be indicated with decreased placental function. A Caesarean section may be performed if there is marked fetal distress or an increased risk of injury associated with macrosomia, such as shoulder dystocia.[citation needed]
Other types

Prediabetes indicates a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of type 2 DM. Many people destined to develop type 2 DM spend many years in a state of prediabetes.

Latent autoimmune diabetes of adults (LADA) is a condition in which type 1 DM develops in adults. Adults with LADA are frequently initially misdiagnosed as having type 2 DM, based on age rather than etiology.

Some cases of diabetes are caused by the body's tissue receptors not responding to insulin (even when insulin levels are normal, which is what separates it from type 2 diabetes); this form is very uncommon. Genetic mutations (autosomal or mitochondrial) can lead to defects in beta cell function. Abnormal insulin action may also have been genetically determined in some cases. Any disease that causes extensive damage to the pancreas may lead to diabetes (for example, chronic pancreatitis and cystic fibrosis). Diseases associated with excessive secretion of insulin-antagonistic hormones can cause diabetes (which is typically resolved once the hormone excess is removed). Many drugs impair insulin secretion and some toxins damage pancreatic beta cells. The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization when the current taxonomy was introduced in 1999.[35]

Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.

"Type 3 diabetes" has been suggested as a term for Alzheimer's disease as the underlying processes may involve insulin resistance by the brain.[36]

The following is a comprehensive list of other causes of diabetes:[37]


Genetic defects of β-cell function

        Maturity onset diabetes of the young
        Mitochondrial DNA mutations

    Genetic defects in insulin processing or insulin action

Defects in proinsulin conversion
    Insulin gene mutations
        Insulin receptor mutations


Exocrine pancreatic defects

      Chronic pancreatitis
        Pancreatectomy
        Pancreatic neoplasia
        Cystic fibrosis
        Hemochromatosis
        Fibrocalculous pancreatopathy



    Endocrinopathies

   Growth hormone excess (acromegaly)
        Cushing syndrome
        Hyperthyroidism
        Pheochromocytoma
        Glucagonoma


Infections

Cytomegalovirus infection
        Coxsackievirus B


Drugs

Glucocorticoids
   Thyroid hormone
   β-adrenergic agonists
   Statins[38]

Pathophysiology

Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, muscle, and adipose tissue. Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.[39]

The body obtains glucose from three main places: the intestinal absorption of food, the breakdown of glycogen, the storage form of glucose found in the liver, and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body.[40] Insulin plays a critical role in balancing glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen.[40]

Insulin is released into the blood by beta cells (β-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Lower glucose levels result in decreased insulin release from the beta cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin.[41]

If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or insulin resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.[40]

When the glucose concentration in the blood remains high over time, the kidneys will reach a threshold of reabsorption, and glucose will be excreted in the urine (glycosuria).[42] This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst (polydipsia).[40]

Diagnosis

Diabetes mellitus is characterized by recurrent or persistent high blood sugar, and is diagnosed by demonstrating any one of the following:[35]

    Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)
    Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a 75 g oral glucose load as in a glucose tolerance test
    Symptoms of high blood sugar and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
    Glycated hemoglobin (HbA1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %).[45]

A positive result, in the absence of unequivocal high blood sugar, should be confirmed by a repeat of any of the above methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test.[46] According to the current definition, two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.

Per the World Health Organization people with fasting glucose levels from 6.1 to 6.9 mmol/l (110 to 125 mg/dl) are considered to have impaired fasting glucose.[47] people with plasma glucose at or above 7.8 mmol/l (140 mg/dl), but not over 11.1 mmol/l (200 mg/dl), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.[48] The American Diabetes Association since 2003 uses a slightly different range for impaired fasting glucose of 5.6 to 6.9 mmol/l (100 to 125 mg/dl).[49]

Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.[50]

The rare disease diabetes insipidus has similar symptoms to diabetes mellitus, but without disturbances in the sugar metabolism (insipidus means "without taste" in Latin) and does not involve the same disease mechanisms. Diabetes is a part of the wider condition known as metabolic syndrome.

Condition	2 hour glucose	Fasting glucose	HbA_1c
Unit	mmol/l(mg/dl)	mmol/l(mg/dl)	mmol/mol	DCCT %
Normal	<7.8 (<140)	<6.1 (<110)	<42	<6.0
Impaired fasting glycaemia	<7.8 (<140)	≥6.1(≥110) & <7.0(<126)	42-46	6.0–6.4
Impaired glucose tolerance	≥7.8 (≥140)	<7.0 (<126)	42-46	6.0–6.4
Diabetes mellitus	≥11.1 (≥200)	≥7.0 (≥126)	≥48	≥6.5

Prevention

There is no known preventive measure for type 1 diabetes.[3] Type 2 diabetes can often be prevented by a person being a normal body weight, physical exercise, and following a healthful diet.[3] Dietary changes known to be effective in helping to prevent diabetes include a diet rich in whole grains and fiber, and choosing good fats, such as polyunsaturated fats found in nuts, vegetable oils, and fish.[51] Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help in the prevention of diabetes.[51] Active smoking is also associated with an increased risk of diabetes, so smoking cessation can be an important preventive measure as well.[52]

Management

Diabetes mellitus is a chronic disease, for which there is no known cure except in very specific situations.[53] Management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly insulin, in type 2 diabetes).

Learning about the disease and actively participating in the treatment is important, since complications are far less common and less severe in people who have well-managed blood sugar levels.[54][55] The goal of treatment is an HbA1C level of 6.5%, but should not be lower than that, and may be set higher.[56] Attention is also paid to other health problems that may accelerate the negative effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.[56] Specialized footwear is widely used to reduce the risk of ulceration, or re-ulceration, in at-risk diabetic feet. Evidence for the efficacy of this remains equivocal, however.[57]

Lifestyle

People with diabetes can benefit from education about the disease and treatment, good nutrition to achieve a normal body weight, and exercise, with the goal of keeping both short-term and long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications are recommended to control blood pressure.[58]

Medications

Medications used to treat diabetes do so by lowering blood sugar levels. There are a number of different classes of anti-diabetic medications. Some are available by mouth, such as metformin, while others are only available by injection such as GLP-1 agonists. Type 1 diabetes can only be treated with insulin, typically with a combination of regular and NPH insulin, or synthetic insulin analogs.[citation needed]

Metformin is generally recommended as a first line treatment for type 2 diabetes, as there is good evidence that it decreases mortality.[59] It works by decreasing the liver's production of glucose.[60] Several other groups of drugs, mostly given by mouth, may also decrease blood sugar in type II DM. These include agents that increase insulin release, agents that decrease absorption of sugar from the intestines, and agents that make the body more sensitive to insulin.[60] When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially, while continuing oral medications.[59] Doses of insulin are then increased to effect.[59][61]

Since cardiovascular disease is a serious complication associated with diabetes, some recommend blood pressure levels below 120/80 mmHg.[62][63] However, evidence supports less than or equal to somewhere between 140/90 mmHg to 160/100 mmHg; the only additional benefit found for blood pressure targets beneath this range was an isolated decrease in stroke risk, and this was accompanied by an increased risk of other serious adverse events.[64][65] Amongst medications that lower blood pressure, angiotensin converting enzyme inhibitors (ACEIs) improve outcomes in those with DM while the similar medications angiotensin receptor blockers (ARBs) do not.[66] Aspirin is also recommended for patient with cardiovascular problems, however routine use of aspirin has not been found to improve outcomes in uncomplicated diabetes.[67]

Surgery

A pancreas transplant is occasionally considered for people with type 1 diabetes who have severe complications of their disease, including end stage kidney disease requiring kidney transplantation.[68]

Weight loss surgery in those with obesity and type two diabetes is often an effective measure.[69] Many are able to maintain normal blood sugar levels with little or no medications following surgery[70] and long-term mortality is decreased.[71] There however is some short-term mortality risk of less than 1% from the surgery.[72] The body mass index cutoffs for when surgery is appropriate are not yet clear.[71] It is recommended that this option be considered in those who are unable to get both their weight and blood sugar under control.[73]

Support

In countries using a general practitioner system, such as the United Kingdom, care may take place mainly outside hospitals, with hospital-based specialist care used only in case of complications, difficult blood sugar control, or research projects. In other circumstances, general practitioners and specialists share care in a team approach. Home telehealth support can be an effective management technique.[74]