DISEASE CAUSES SYMPTOMS
Diabetes mellitus
commonly known as diabetes, is a group of metabolic disorders characterized by a high blood sugar level over a prolonged period of time.[11] Symptoms often include frequent urination, increased thirst, and increased appetite.[2] If left untreated, diabetes can cause many complications.[2] Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death.[3] Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, damage to the nerves, damage to the eyes and cognitive impairment.[2][5]
Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced.[12] There are three main types of diabetes mellitus:[2]
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Type 1 diabetes results from the pancreas's failure to produce enough insulin due to loss of beta cells.[2] This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".[2] The loss of beta cells is caused by an autoimmune response.[13] The cause of this autoimmune response is unknown.[2]
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Type 2 diabetes begins with insulin resistance, a condition in which cells fail to respond to insulin properly.[2] As the disease progresses, a lack of insulin may also develop.[14] This form was previously referred to as "non insulin-dependent diabetes mellitus" (NIDDM) or "adult-onset diabetes".[2] The most common cause is a combination of excessive body weight and insufficient exercise.[2]
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Gestational diabetes is the third main form, and occurs when pregnant women without a previous history of diabetes develop high blood sugar levels.[2]
Type 1 diabetes must be managed with insulin injections.[2] Prevention and treatment of type 2 diabetes involves maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco.[2] Type 2 diabetes may be treated with medications such as insulin sensitizers with or without insulin.[15] Control of blood pressure and maintaining proper foot and eye care are important for people with the disease.[2] Insulin and some oral medications can cause low blood sugar.[16] Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 diabetes.[17] Gestational diabetes usually resolves after the birth of the baby.[18]
As of 2019, an estimated 463 million people had diabetes worldwide (8.8% of the adult population), with type 2 diabetes making up about 90% of the cases.[10] Rates are similar in women and men.[19] Trends suggest that rates will continue to rise.[10] Diabetes at least doubles a person's risk of early death.[2] In 2019, diabetes resulted in approximately 4.2 million deaths.[10] It is the 7th leading cause of death globally.[20][21] The global economic cost of diabetes related health expenditure in 2017 was estimated at US$727 billion.[10] In the United States, diabetes cost nearly US$327 billion in 2017.[22] Average medical expenditures among people with diabetes are about 2.3 times higher
Signs and symptoms
The classic symptoms of untreated diabetes are unintended weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger).[24] Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.[25]
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 blurred 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. Long-term vision loss can also be caused by diabetic retinopathy. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes
Diabetic emergencies
People (usually with type 1 diabetes) may also experience episodes of diabetic ketoacidosis (DKA), 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.[27] A rare but equally severe possibility is hyperosmolar hyperglycemic state (HHS), which is more common in type 2 diabetes and is mainly the result of dehydration.[27]
Treatment-related low blood sugar (hypoglycemia) is common in people with type 1 and also type 2 diabetes depending on the medication being used. 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 effects such as confusion, changes in behavior such as aggressiveness, seizures, unconsciousness, and (rarely) permanent brain damage or death in severe cases.[28][29] Rapid breathing, sweating, and cold, pale skin are characteristic of low blood sugar but not definitive.[30] Mild to moderate 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
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[32] and about 75% of deaths in people with diabetes are due to coronary artery disease.[33] Other macrovascular diseases include stroke, and peripheral artery disease.
The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves.[34] 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 eventual blindness.[34] Diabetes also increases the risk of having glaucoma, cataracts, and other eye problems. It is recommended that people with diabetes visit an eye doctor once a year.[35] 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 transplantation.[34] Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes.[34] 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 atrophy 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.[36] Having diabetes, especially when on insulin, increases the risk of falls in older people
Causes
Type 1
Type 1 diabetes is characterized by loss of the insulin-producing beta cells of the pancreatic islets, 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.[42] 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. Although it has been called "juvenile diabetes" due to the frequent onset in children, the majority of individuals living with type 1 diabetes are now adults.[6]
"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.[43] Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, and the potential for diabetic ketoacidosis or 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).[43] These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.[44]
Autoimmune attack in type 1 diabetes.
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,[45] such as a viral infection or diet. Several viruses have been implicated, but to date there is no stringent evidence to support this hypothesis in humans.[45][46] Among dietary factors, data suggest that gliadin (a protein present in gluten) may play a role in the development of type 1 diabetes, but the mechanism is not fully understood.[47][48]
Type 1 diabetes can occur at any age, and a significant proportion is diagnosed during adulthood. Latent autoimmune diabetes of adults (LADA) is the diagnostic term applied when type 1 diabetes develops in adults; it has a slower onset than the same condition in children. Given this difference, some use the unofficial term "type 1.5 diabetes" for this condition. Adults with LADA are frequently initially misdiagnosed as having type 2 diabetes, based on age rather than cause
Type 2
Type 2 diabetes is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion.[12] 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 diabetes is the most common type of diabetes mellitus.[2] Many people with type 2 diabetes have evidence of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) before meeting the criteria for type 2 diabetes.[50] The progression of prediabetes to overt type 2 diabetes can be slowed or reversed by lifestyle changes or medications that improve insulin sensitivity or reduce the liver's glucose production.[51]
Type 2 diabetes is primarily due to lifestyle factors and genetics.[52] A number of lifestyle factors are known to be important to the development of type 2 diabetes, including obesity (defined by a body mass index of greater than 30), lack of physical activity, poor diet, stress, and urbanization.[38] Excess body fat is associated with 30% of cases in people of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of Pima Indians and Pacific Islanders.[12] Even those who are not obese may have a high waist–hip ratio.[12]
Dietary factors such as sugar-sweetened drinks is associated with an increased risk.[53][54] The type of fats in the diet is also important, with saturated fat and trans fats increasing the risk and polyunsaturated and monounsaturated fat decreasing the risk.[52] Eating white rice excessively may increase the risk of diabetes, especially in Chinese and Japanese people.[55] Lack of physical activity may increase the risk of diabetes in some people.[56]
Adverse childhood experiences (ACEs), including abuse, neglect, and household difficulties, increase the likelihood of type 2 diabetes later in life by 32%, with neglect having the strongest effect
Gestational diabete
Gestational diabetes resembles type 2 diabetes 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.[58] It is recommended that all pregnant women get tested starting around 24–28 weeks gestation.[59] It is most often diagnosed in the second or third trimester because of the increase in insulin-antagonist hormone levels that occurs at this time.[59] However, after pregnancy approximately 5–10% of women with gestational diabetes are found to have another form of diabetes, most commonly type 2.[58] 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[60]
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 infant 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.[61]
Other types
Maturity onset diabetes of the young (MODY) is a rare autosomal dominant inherited form of diabetes, due to one of several single-gene mutations causing defects in insulin production.[62] It is significantly less common than the three main types, constituting 1-2% of all cases. The name of this disease refers to early hypotheses as to its nature. Being due to a defective gene, this disease varies in age at presentation and in severity according to the specific gene defect; thus there are at least 13 subtypes of MODY. People with MODY often can control it without using insulin.[63]
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, whereas others increase insulin resistance (especially glucocorticoids which can provoke "steroid diabetes"). The ICD-10 (1992) diagnostic entity, malnutrition-related diabetes mellitus (MRDM or MMDM, ICD-10 code E12), was deprecated by the World Health Organization (WHO) when the current taxonomy was introduced in 1999.[64]
The following is a list of disorders that may increase the risk of diabetes
Pathophysiology
The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals. One of the effects of a sugar-rich vs a starch-rich meal is highlighted.
Mechanism of insulin release in normal pancreatic beta cells. Insulin production is more or less constant within the beta cells. Its release is triggered by food, chiefly food containing absorbable glucose.
Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, adipose tissue and muscle, except smooth muscle, in which insulin acts via the IGF-1. Therefore, deficiency of insulin or the insensitivity of its receptors play a central role in all forms of diabetes mellitus.[67]
The body obtains glucose from three main sources: the intestinal absorption of food; the breakdown of glycogen (glycogenolysis), the storage form of glucose found in the liver; and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body.[68] Insulin plays a critical role in regulating 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.[68]
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.[69]
If the amount of insulin available is insufficient, or if cells respond poorly to the effects of insulin (insulin resistance), or if the insulin itself is defective, then glucose is not absorbed properly by the body cells that require it, and is not 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 metabolic acidosis in cases of complete insulin deficiency.[68]
When glucose concentration in the blood remains high over time, the kidneys reach a threshold of reabsorption, and the body excretes glucose in the urine (glycosuria).[70] 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 is replaced osmotically from water in body cells and other body compartments, causing dehydration and increased thirst (polydipsia).[68] In addition, intracellular glucose deficiency stimulates appetite leading to excessive food intake
Diagnosis
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.[75] According to the current definition, two fasting glucose measurements above 7.0 mmol/L (126 mg/dL) is considered diagnostic for diabetes mellitus.
Per the WHO, 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.[76] 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 gram 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.[77] The American Diabetes Association (ADA) since 2003 uses a slightly different range for impaired fasting glucose of 5.6 to 6.9 mmol/L
Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.
Prevention
There is no known preventive measure for type 1 diabetes.[2] Type 2 diabetes—which accounts for 85–90% of all cases worldwide—can often be prevented or delayed by maintaining a normal body weight, engaging in physical activity, and eating a healthy diet.[2] Higher levels of physical activity (more than 90 minutes per day) reduce the risk of diabetes by 28%.[80] Dietary changes known to be effective in helping to prevent diabetes include maintaining a diet rich in whole grains and fiber, and choosing good fats, such as the polyunsaturated fats found in nuts, vegetable oils, and fish.[81] Limiting sugary beverages and eating less red meat and other sources of saturated fat can also help prevent diabetes.[81] Tobacco smoking is also associated with an increased risk of diabetes and its complications, so smoking cessation can be an important preventive measure as well.[82]
The relationship between type 2 diabetes and the main modifiable risk factors (excess weight, unhealthy diet, physical inactivity and tobacco use) is similar in all regions of the world. There is growing evidence that the underlying determinants of diabetes are a reflection of the major forces driving social, economic and cultural change: globalization, urbanization, population aging, and the general health policy environment.
Management
Overview of the management of diabetes
Diabetes management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with dietary changes, exercise, weight loss, and use of appropriate medications (insulin, oral medications).
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.[84][85] Per the American College of Physicians, the goal of treatment is an HbA1C level of 7-8%.[86] Attention is also paid to other health problems that may accelerate the negative effects of diabetes. These include smoking, high blood pressure, metabolic syndrome obesity, and lack of regular exercise.[87] Specialized footwear is widely used to reduce the risk of ulcers in at-risk diabetic feet although evidence for the efficacy of this remains equivocal.[88]
Lifestyle
People with diabetes can benefit from education about the disease and treatment, dietary changes, 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.[89][90]
Weight loss can prevent progression from prediabetes to diabetes type 2, decrease the risk of cardiovascular disease, or result in a partial remission in people with diabetes.[91][92] No single dietary pattern is best for all people with diabetes.[93] Healthy dietary patterns, such as the Mediterranean diet, low-carbohydrate diet, or DASH diet are often recommended, although evidence does not support one over the others.[91][92] According to the ADA, "reducing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia", and for individuals with type 2 diabetes who can not meet the glycemic targets or where reducing anti-glycemic medications is a priority, low or very-low carbohydrate diets are a viable approach.[92] For overweight people with type 2 diabetes, any diet that achieves weight loss is effective.[93][94]
Medications
Most medications used to treat diabetes act by lowering blood sugar levels through different mechanisms. There is broad consensus that when people with diabetes maintain tight glucose control – keeping the glucose levels in their blood within normal ranges – they experience fewer complications, such as kidney problems or eye problems.[95][96] There is however debate as to whether this is appropriate and cost effective for people later in life in whom the risk of hypoglycemia may be more significant.[97]
There are a number of different classes of anti-diabetic medications. Type 1 diabetes requires treatment with insulin, typically with a combination of regular and NPH insulin, or synthetic insulin analogs.[citation needed] Type 2 diabetes may also be treated with insulin at later stages. Some medications for type 2 diabetes are taken by mouth, such as metformin, while others are only administered by injection, such as GLP-1 agonists.
Metformin is generally recommended as a first-line treatment for type 2 diabetes, as there is good evidence that it decreases mortality.[8] It works by decreasing the liver's production of glucose.[98] Several other groups of drugs, mostly given by mouth, may also decrease blood sugar in type 2 diabetes. These include agents that increase insulin release (sulfonylureas), agents that decrease absorption of sugar from the intestines (acarbose), agents that inhibit the enzyme dipeptidyl peptidase-4 (DPP-4) that inactivates incretins such as GLP-1 and GIP (sitagliptin), agents that make the body more sensitive to insulin (thiazolidinedione) and agents that increase the excretion of glucose in the urine (SGLT2 inhibitors).[98] When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially, while continuing oral medications.[8] Doses of insulin are then increased until glucose targets are reached
Hypertension
also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated.[10] High blood pressure typically does not cause symptoms.[1] Long-term high blood pressure, however, is a major risk factor for coronary artery disease, stroke, heart failure, atrial fibrillation, peripheral arterial disease, vision loss, chronic kidney disease, and dementia.[2][3][4][11]
High blood pressure is classified as primary (essential) hypertension or secondary hypertension.[5] About 90–95% of cases are primary, defined as high blood pressure due to nonspecific lifestyle and genetic factors.[5][6] Lifestyle factors that increase the risk include excess salt in the diet, excess body weight, smoking, and alcohol use.[1][5] The remaining 5–10% of cases are categorized as secondary high blood pressure, defined as high blood pressure due to an identifiable cause, such as chronic kidney disease, narrowing of the kidney arteries, an endocrine disorder, or the use of birth control pills.[5]
Blood pressure is expressed by two measurements, the systolic and diastolic pressures, which are the maximum and minimum pressures, respectively.[1] For most adults, normal blood pressure at rest is within the range of 100–130 millimeters mercury (mmHg) systolic and 60–80 mmHg diastolic.[7][12] For most adults, high blood pressure is present if the resting blood pressure is persistently at or above 130/80 or 140/90 mmHg.[5][7] Different numbers apply to children.[13] Ambulatory blood pressure monitoring over a 24-hour period appears more accurate than office-based blood pressure measurement.[5][10]
Lifestyle changes and medications can lower blood pressure and decrease the risk of health complications.[8] Lifestyle changes include weight loss, physical exercise, decreased salt intake, reducing alcohol intake, and a healthy diet.[5] If lifestyle changes are not sufficient then blood pressure medications are used.[8] Up to three medications can control blood pressure in 90% of people.[5] The treatment of moderately high arterial blood pressure (defined as >160/100 mmHg) with medications is associated with an improved life expectancy.[14] The effect of treatment of blood pressure between 130/80 mmHg and 160/100 mmHg is less clear, with some reviews finding benefit[7][15][16] and others finding unclear benefit.[17][18][19] High blood pressure affects between 16 and 37% of the population globally.[5] In 2010 hypertension was believed to have been a factor in 18% of all deaths (9.4 million globally)
Signs and symptoms[edit]
Hypertension is rarely accompanied by symptoms, and its identification is usually through screening, or when seeking healthcare for an unrelated problem. Some people 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.[20] These symptoms, however, might be related to associated anxiety rather than the high blood pressure itself.[21]
On physical examination, hypertension may be associated with the presence of changes in the optic fundus seen by ophthalmoscopy.[22] The severity of the changes typical of hypertensive retinopathy is graded from I to IV; grades I and II may be difficult to differentiate.[22] The severity of the retinopathy correlates roughly with the duration or the severity of the hypertension.[20]
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 (referred to as a buffalo hump), and purple abdominal stretch marks.[23] 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, or delayed or absent femoral arterial pulses. Pheochromocytoma may cause abrupt ("paroxysmal") episodes of hypertension accompanied by headache, palpitations, pale appearance, and excessive sweating.
Hypertensive crisis
Main article: 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.[24][25]
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.[26]
In hypertensive emergency, there is evidence of direct damage to one or more organs.[27][28] The most affected organs include the brain, kidney, heart and lungs, producing symptoms which may include confusion, drowsiness, chest pain and breathlessness.[26] In hypertensive emergency, the blood pressure must be reduced more rapidly to stop ongoing organ damage,[26] however, there is a lack of randomized controlled trial evidence for this approach.[28]
Pregnancy
Main articles: Gestational hypertension and Pre-eclampsia
Hypertension occurs in approximately 8–10% of pregnancies.[23] Two blood pressure measurements six hours apart of greater than 140/90 mm Hg are diagnostic of hypertension in pregnancy.[29] High blood pressure in pregnancy can be classified as pre-existing hypertension, gestational hypertension, or pre-eclampsia.[30]
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.[23] It occurs in about 5% of pregnancies and is responsible for approximately 16% of all maternal deaths globally.[23] Pre-eclampsia also doubles the risk of death of the baby around the time of birth.[23] 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).[23][31]
In contrast, gestational hypertension is defined as new-onset hypertension during pregnancy without protein in the urine.[30]
Children
Failure to thrive, seizures, irritability, lack of energy, and difficulty in breathing[32] can be associated with hypertension in newborns and young infants. In older infants and children, hypertension can cause headache, unexplained irritability, fatigue, failure to thrive, blurred vision, nosebleeds, and facial paralysis.[32][33]
Causes[edit]
Primary hypertension
Main article: Essential 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[34] as well as some rare genetic variants with large effects on blood pressure.[35] Also, genome-wide association studies (GWAS) have identified 35 genetic loci related to blood pressure; 12 of these genetic loci influencing blood pressure were newly found.[36] Sentinel SNP for each new genetic locus identified has shown an association with DNA methylation at multiple nearby CpG sites. These sentinel SNP are located within genes related to vascular smooth muscle and renal function. DNA methylation might affect in some way linking common genetic variation to multiple phenotypes even though mechanisms underlying these associations are not understood. Single variant test performed in this study for the 35 sentinel SNP (known and new) showed that genetic variants singly or in aggregate contribute to risk of clinical phenotypes related to high blood pressure.[36]
Blood pressure rises with aging and the risk of becoming hypertensive in later life is significant.[37] Several environmental factors influence blood pressure. High salt intake raises the blood pressure in salt sensitive individuals; lack of exercise, central obesity can play a role in individual cases. The possible roles of other factors such as caffeine consumption,[38] and vitamin D deficiency[39] are less clear. Insulin resistance, which is common in obesity and is a component of syndrome X (or the metabolic syndrome), also contributes to hypertension.[40] One review suggests that sugar may play an important role in hypertension and salt is just an innocent bystander.[41]
Events in early life, such as low birth weight, maternal smoking, and lack of breastfeeding may be risk factors for adult essential hypertension, although the mechanisms linking these exposures to adult hypertension remain unclear.[42] An increased rate of high blood uric acid has been found in untreated people with hypertension 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.[43] Average blood pressure may be higher in the winter than in the summer.[44] Periodontal disease is also associated with high blood pressure.[45]
Secondary hypertension
Main article: Secondary hypertension
Secondary hypertension results from an identifiable cause. Kidney disease is the most common secondary cause of hypertension.[23] Hypertension can also be caused by endocrine conditions, such as Cushing's syndrome, hyperthyroidism, hypothyroidism, acromegaly, Conn's syndrome or hyperaldosteronism, renal artery stenosis (from atherosclerosis or fibromuscular dysplasia), hyperparathyroidism, and pheochromocytoma.[23][46] Other causes of secondary hypertension include obesity, sleep apnea, pregnancy, coarctation of the aorta, excessive eating of liquorice, excessive drinking of alcohol, certain prescription medicines, herbal remedies, and stimulants such as cocaine and methamphetamine.[23][47] Arsenic exposure through drinking water has been shown to correlate with elevated blood pressure.[48][49] Depression was also linked to hypertension.[50] Loneliness is also a risk factor.[51]
A 2018 review found that any alcohol increased blood pressure in males while over one or two drinks increased the risk in females.[52]
Pathophysiology
Main article: Pathophysiology of hypertension
Illustration depicting the effects of high blood pressure
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.[53] 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.[54] These individuals develop the typical features of established essential hypertension in later life as their cardiac output falls and peripheral resistance rises with age.[54] Whether this pattern is typical of all people who ultimately develop hypertension is disputed.[55] The increased peripheral resistance in established hypertension is mainly attributable to structural narrowing of small arteries and arterioles,[56] although a reduction in the number or density of capillaries may also contribute.[57]
It is not clear whether or not vasoconstriction of arteriolar blood vessels plays a role in hypertension.[58] Hypertension is also associated with decreased peripheral venous compliance[59] 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.[60] 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.[61]
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)[62] or abnormalities of the sympathetic nervous system.[63] 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.[64][65] 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.[66]
Excessive sodium or insufficient potassium in the diet leads to excessive intracellular sodium, which contracts vascular smooth muscle, restricting blood flow and so increases blood pressure.[67][68]
Diagnosis
Hypertension is diagnosed on the basis of a persistently high resting blood pressure. The American Heart Association recommends at least three resting measurements on at least two separate health care visits.[69] The UK National Institute for Health and Care Excellence recommends ambulatory blood pressure monitoring to confirm the diagnosis of hypertension if a clinic blood pressure is 140/90 mmHg or higher
Hypercholesterolemia
also called high cholesterol, is the presence of high levels of cholesterol in the blood.[1] It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia (elevated levels of lipoproteins in the blood).[1]
Elevated levels of non-HDL cholesterol and LDL in the blood may be a consequence of diet, obesity, inherited (genetic) diseases (such as LDL receptor mutations in familial hypercholesterolemia), or the presence of other diseases such as type 2 diabetes and an underactive thyroid.[1]
Cholesterol is one of three major classes of lipids which all animal cells use to construct their membranes and is thus manufactured by all animal cells. Plant cells do manufacture cholesterol, but in rather small quantities.[2] It is also the precursor of the steroid hormones and bile acids. Since cholesterol is insoluble in water, it is transported in the blood plasma within protein particles (lipoproteins). Lipoproteins are classified by their density: very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL).[3] All the lipoproteins carry cholesterol, but elevated levels of the lipoproteins other than HDL (termed non-HDL cholesterol), particularly LDL-cholesterol, are associated with an increased risk of atherosclerosis and coronary heart disease.[4] In contrast, higher levels of HDL cholesterol are protective.[5]
Avoiding trans fats and replacing saturated fats in adult diets with polyunsaturated fats are recommended dietary measures to reduce total blood cholesterol and LDL in adults.[6][7] In people with very high cholesterol (e.g., familial hypercholesterolemia), diet is often not sufficient to achieve the desired lowering of LDL, and lipid-lowering medications are usually required.[8] If necessary, other treatments such as LDL apheresis or even surgery (for particularly severe subtypes of familial hypercholesterolemia) are performed.[8] About 34 million adults in the United States have high blood cholesterol
Signs and symptoms
Although hypercholesterolemia itself is asymptomatic, longstanding elevation of serum cholesterol can lead to atherosclerosis (hardening of arteries).[10] Over a period of decades, elevated serum cholesterol contributes to formation of atheromatous plaques in the arteries. This can lead to progressive narrowing of the involved arteries. Alternatively smaller plaques may rupture and cause a clot to form and obstruct blood flow.[11] A sudden blockage of a coronary artery may result in a heart attack. A blockage of an artery supplying the brain can cause a stroke. If the development of the stenosis or occlusion is gradual, blood supply to the tissues and organs slowly diminishes until organ function becomes impaired. At this point tissue ischemia (restriction in blood supply) may manifest as specific symptoms. For example, temporary ischemia of the brain (commonly referred to as a transient ischemic attack) may manifest as temporary loss of vision, dizziness and impairment of balance, difficulty speaking, weakness or numbness or tingling, usually on one side of the body. Insufficient blood supply to the heart may cause chest pain, and ischemia of the eye may manifest as transient visual loss in one eye. Insufficient blood supply to the legs may manifest as calf pain when walking, while in the intestines it may present as abdominal pain after eating a meal.[1][12]
Some types of hypercholesterolemia lead to specific physical findings. For example, familial hypercholesterolemia (Type IIa hyperlipoproteinemia) may be associated with xanthelasma palpebrarum (yellowish patches underneath the skin around the eyelids),[13] arcus senilis (white or gray discoloration of the peripheral cornea),[14] and xanthomata (deposition of yellowish cholesterol-rich material) of the tendons, especially of the fingers.[15][16] Type III hyperlipidemia may be associated with xanthomata of the palms, knees and elbows.[15]
Causes
Medical conditions and treatments
A number of other conditions can also increase cholesterol levels including diabetes mellitus type 2, obesity, alcohol use, monoclonal gammopathy, dialysis therapy, nephrotic syndrome, hypothyroidism, Cushing’s syndrome and anorexia nervosa.[10] Several medications and classes of medications may interfere with lipid metabolism: thiazide diuretics, ciclosporin, glucocorticoids, beta blockers, retinoic acid, antipsychotics),[10] certain anticonvulsants and medications for HIV as well as interferons.[19]
Genetics
Genetic contributions are usually due to the additive effects of multiple genes ("polygenic"), though occasionally may be due to a single gene defect such as in the case of familial hypercholesterolaemia.[10] In familial hypercholesterolemia, mutations may be present in the APOB gene (autosomal dominant), the autosomal recessive LDLRAP1 gene, autosomal dominant familial hypercholesterolemia (HCHOLA3) variant of the PCSK9 gene, or the LDL receptor gene.[20] Familial hypercholesterolemia affects about one in five hundred people.[9]
Diet
Diet has an effect on blood cholesterol, but the size of this effect varies between individuals.[21][22] Moreover, when dietary cholesterol intake goes down, production (principally by the liver)[23] typically increases, so that blood cholesterol changes can be modest[24] or even elevated. This compensatory response may explain hypercholesterolemia in anorexia nervosa. A 2016 review found tentative evidence that dietary cholesterol is associated with higher blood cholesterol.[25] Trans fats have been shown to reduce levels of HDL while increasing levels of LDL.[26] LDL and total cholesterol also increases by very high fructose intake.[27]
As of 2018 there appears to be a modest positive, dose-related relationship between cholesterol intake and LDL cholesterol.[28]
Diagnosis
Cholesterol is measured in milligrams per deciliter (mg/dL) of blood in the United States and some other countries. In the United Kingdom, most European countries and Canada, millimoles per liter of blood (mmol/Ll) is the measure.[30]
For healthy adults, the UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L. For people at high risk of cardiovascular disease, the recommended limit for total cholesterol is 4 mmol/L, and 2 mmol/L for LDL.[31]
In the United States, the National Heart, Lung, and Blood Institute within the National Institutes of Health classifies total cholesterol of less than 200 mg/dL as “desirable,” 200 to 239 mg/dL as “borderline high,” and 240 mg/dL or more as “high”.[32]
No absolute cutoff between normal and abnormal cholesterol levels exists, and interpretation of values must be made in relation to other health conditions and risk factors.
Higher levels of total cholesterol increase the risk of cardiovascular disease, particularly coronary heart disease.[33] Levels of LDL or non-HDL cholesterol both predict future coronary heart disease; which is the better predictor is disputed.[34] High levels of small dense LDL may be particularly adverse, although measurement of small dense LDL is not advocated for risk prediction.[34] In the past, LDL and VLDL levels were rarely measured directly due to cost. Levels of fasting triglycerides were taken as an indicator of VLDL levels (generally about 45% of fasting triglycerides is composed of VLDL), while LDL was usually estimated by the Friedewald formula:
LDL {\displaystyle \approx } total cholesterol - HDL - (0.2 x fasting triglycerides).
However, this equation is not valid on nonfasting blood samples or if fasting triglycerides are elevated >4.5 mmol/L (> ∼400 mg/dL). Recent guidelines have, therefore, advocated the use of direct methods for measurement of LDL wherever possible.[34] It may be useful to measure all lipoprotein subfractions ( VLDL, IDL, LDL, and HDL) when assessing hypercholesterolemia and measurement of apolipoproteins and lipoprotein (a) can also be of value.[34] Genetic screening is now advised if a form of familial hypercholesterolemia is suspected