Kwashiorkor
Kwashiorkor ( KWOSH-ee-OR-kor, -⁠kər, UK also  KWASH-) is a form of severe protein malnutrition characterized by edema and an enlarged liver with fatty infiltrates. It is thought to be caused by sufficient calorie intake, but with insufficient protein consumption (or lack of good quality protein), which distinguishes it from marasmus. Recent studies have found that a lack of antioxidant micronutrients such as β-carotene, lycopene, other carotenoids, and vitamin C as well as the presence of aflatoxins may play a role in the development of the disease. However, the exact cause of kwashiorkor is still unknown. Inadequate food supply is correlated with occurrences of kwashiorkor; occurrences in high income countries are rare.  It occurs amongst weaning children to ages of about five years old.Conditions analogous to kwashiorkor were well documented around the world throughout history. However, Jamaican pediatrician Cicely Williams introduced the term in 1935, two years after she published the diseases first formal description. Williams was the first to conduct research on kwashiorkor and differentiate it from other dietary deficiencies. She was the first to suggest that this might be a deficiency of protein.  The name is derived from the Ga language of coastal Ghana, translated as "the sickness the baby gets when the new baby comes" or "the disease of the deposed child", and reflecting the development of the condition in an older child who has been weaned from the breast when a younger sibling comes. Breast milk contains amino acids vital to a childs growth. In at-risk populations, kwashiorkor may develop after children are weaned from breast milk and begin consuming a diet high in carbohydrates, including maize, cassava or rice.

Classification
Children with severe malnutrition have an increased risk of serious illness and death.
Kwashiorkor is one of the main forms of childhood malnutrition living in low-income and middle-income countries. Kwashiorkor is oftentimes referred to as severe acute malnutrition (SAM). Severe forms of malnutritions are recognized, including stunting, marasmus, and kwashiorkor. Both kwashiorkor and marasmus fall under the umbrella of deficiencies called protein–energy malnutrition (PEM). These diseases are oftentimes discussed together, but can be distinguished. Kwashiorkor is classified by its insufficient protein consumption whereas marasmus is related to general energy deficiency and severe muscle wasting. Kwashiorkor is also distinguished from marasmus by the presence of edema. There is also marasmic kwashiorkor that is the deficiency in calories and in protein. Although they are both different types of severe acute malnutrition, there was greater consumption of antioxidants, vitamins, and minerals seen in those with kwashiorkor compared to those with marasmus.

Wellcomes classification
Wellcome classification is a system for classifying protein-energy malnutrition in children based on weight for their age and based on presence of edema. Other classifications include Gomez classification and Waterlow classification.

Signs and symptoms
The defining sign of kwashiorkor in a malnourished child is pitting edema (particularly swelling of the hands and feet). Unlike marasmus, where the liver and other essential organs are reduced in size, kwashiorkor is characterized by "an enlarged fatty liver, fibrosis, and dysfunction of several organs (such as the liver, kidneys, and nervous system)".  Other signs include a distended abdomen, thinning of hair, loss of teeth, skin or hair depigmentation, and dermatitis. Children with kwashiorkor often develop irritability and anorexia. Generally, the disease can be treated by adding protein to the diet; however, it can have a long-term impact on a childs physical and mental development, and in severe cases may lead to death.In dry climates, marasmus is the more frequent disease associated with malnutrition. Another malnutrition syndrome includes cachexia, although it is often caused by underlying illnesses.  These are important considerations in the treatment of individuals with kwashiorkor.

Causes
The precise etiology of kwashiorkor remains unclear. Several hypotheses have been proposed that are associated with and explain some, but not all aspects of the pathophysiology of kwashiorkor. They include, but are not limited to protein deficiency causing hypoalbuminemia, amino acid deficiency, oxidative stress, and gut microbiome changes.

Low protein intake
Kwashiorkor is a severe form of malnutrition associated with a deficiency in dietary protein. The extreme lack of protein causes an osmotic imbalance in the gastrointestinal system causing swelling of the gut diagnosed as an edema or retention of water.Extreme fluid retention observed in individuals suffering from kwashiorkor is a direct result of irregularities in the lymphatic system and an indication of capillary exchange. The lymphatic system serves three major purposes: fluid recovery, immunity, and lipid absorption. Victims of kwashiorkor commonly exhibit reduced ability to recover fluids, immune system failure, and low lipid absorption, all of which result from a state of severe undernourishment. Fluid recovery in the lymphatic system is accomplished by re-absorption of water and proteins which are then returned to the blood. Compromised fluid recovery results in the characteristic belly distension observed in highly malnourished children.Capillary exchange between the lymphatic system and the bloodstream is stunted due to the inability of the body to effectively overcome the hydrostatic pressure gradient. Proteins, mainly albumin, are responsible for creating the colloid osmotic pressure (COP) observed in the blood and tissue fluids. The difference in the COP of the blood and tissue is called the oncotic pressure. The oncotic pressure is in direct opposition with the hydrostatic pressure and tends to draw water back into the capillary by osmosis. However, due to the lack of proteins, no substantial pressure gradient can be established to draw fluids from the tissue back into the blood stream. This results in the pooling of fluids, causing the swelling and distention of the abdomen.The low protein intake leads to some specific signs: edema of the hands and feet, irritability, anorexia, a desquamative rash, hair discolouration, and a large fatty liver. The typical swollen abdomen is due to two causes: ascites because of hypoalbuminemia (low oncotic pressure), and enlarged fatty liver.Ignorance of nutrition can be a cause. A case was described where parents who fed their child cassava failed to recognize malnutrition because of the edema caused by the syndrome and believed the child was well-nourished despite the lack of dietary protein.Protein should be supplied only for anabolic purposes. The catabolic needs should be satisfied with carbohydrate and fat. Protein catabolism involves the urea cycle, which is located in the liver and can easily overwhelm the capacity of an already damaged organ. The resulting liver failure can be fatal.  This means in individuals suffering from kwashiorkor, protein must be introduced back into the diet gradually. Clinical solutions include weaning the affected with milk products and increasing the intake of proteinaceous material progressively to daily recommended amounts.

Aflatoxins
Recent studies have attempted to pinpoint a relationship between kwashiorkor and high levels of aflatoxins. Aflatoxins are naturally occurring toxins produced by the mold Aspergillus flavus, a fungus found in areas with hot and humid climates. These toxins tend to grow and can be found in agricultural crops such as millet, maize, and rice. An analysis found that the presence of aflatoxins was found more frequently and in higher concentrations in individuals with kwashiorkor when compared to individuals with marasmus (another form of severe acute malnutrition). In particular, biological samples showed greater levels of aflatoxins in the brain, heart, kidney, liver, lungs, serum, stool, and urine. Aflatoxins were not found in liver samples of individuals with marasmus. It has been known that the liver organ is the main target of aflatoxins and chronic toxicity can result in immunosuppressive and carcinogenic effects. However, there is currently conflicting evidence to pinpoint a connection between kwashiorkor and aflatoxins. Studies have shown that not all children with kwashiorkor present with detectable aflatoxin levels. It has also been proposed that damage done by aflatoxins may be due to glutathione depletion (another proposed mechanism of the disease) in children with kwashiorkor.

Mechanisms
Peripheral edema and hypoalbuminemia
Kwashiorkor is a form of protein deficiency, which can result in both osmotic imbalances and irregularities in the lymphatic system.Kwashiorkor is most notable for peripheral edema. The presence of edema in kwashiorkor is correlated with very low albumin concentration (hypoalbuminemia). Edema results from a loss of fluid balance between the hydrostatic and oncotic pressures across the capillary blood vessel walls due to the lack of protein which affects the bodys ability to draw fluid from the tissues into the bloodstream. Low albumin concentration influences negatively the strength of oncotic pressure. Failure leads to the fluid buildup in the abdomen, resulting in edema and belly distension.Furthermore, the release of antidiuretic hormone is stimulated by hypovolemia, also leading to the development of peripheral edema. Plasma renin is also stimulated, promoting sodium retention.It is important to distinguish the pathophysiology of marasmus and kwashiorkor when it comes to treating malnourished children who may have hypovolemic shock that is cause by an acute loss of salt and water. Children with severe albumin deficiency struggle physiologically to maintain their blood volume.

Low glutathione levels
Kwashiorkor is also marked by low glutathione levels. Glutathione is used in many of the body processes on a molecule level.It is believed to be related to high oxidant levels commonly seen in people who suffer from starvation and rarely in chronic inflammation. Glutathione serves vital functions including management of oxidative stress which is an imbalance that plays a key role in the pathogenesis of many diseases.
Cysteine is an essential amino acid that acts as the limiting amino acid for glutathione synthesis in humans. Factors that stimulate cysteine uptake by cells will increase glutathione levels and prevent glutathione deficiency in humans under various conditions including protein malnutrition.Evidence indicates that dietary amino acids balance has an important effect on protein nutrition and therefore on glutathione homeostasis.

Others
A proposed experimental theory suggests that alterations in the microbiome/virone contributes to edematous malnutrition, but further studies are required to understand the mechanism.

Diagnosis
Kwashiorkor, or edematous malnutrition, like many other malnutrition diseases, is indirectly assessed using anthropometry. Kwashiorkor is a subtype of severe acute malnutrition (SAM) characterized by bilateral peripheral pitting edema. According to the World Health Organization, the SAM diagnosis parameters are a "mid-upper arm circumference (MUAC) of < 115 mm, weight-for-height/length Z-score (WHZ) of < -3Z and nutritional edema or any combination of these parameters." Additional clinical findings on physical exam include marked muscle atrophy, abdominal distension, dermatitis, and hepatomegaly.WHO criteria for clinical assessment of malnutrition are based on the degree of wasting (MUAC), stunting (weight-for-height Z-score), and the presence of edema (mild to severe).

Screening
Because it can be difficult to measure weight-for-height Z scores (WHZ) frequently, screening is performed using mid-upper arm circumference (MUAC) < 115 mm. To properly screen for severe malnutrition in children, MUAC measurements should be done every month to reduce the risk of complications. Additionally, getting a better sense of what they eat, how often they eat, and any issues they may have with eating, may give more insight on their nutrition and what changes may need to be made to improve it.

Prevention
As for the prevention of childhood malnutrition, there needs to be public health changes such as improving agriculture and improving access to healthcare to effectively reduce the rates of malnutrition in children. By educating individuals of childbearing age on proper nutrition and health during and after pregnancy, they can provide their children with the appropriate nutrients from a young age. By ensuring they are equipped with the proper education and resources, caretakers and infants are in better health, ultimately preventing childhood malnutrition.Because edema can hide decreased muscle mass, it can be hard to diagnose kwashiorkor in young children; however, if cases are overlooked, children become more susceptible to infections and can ultimately lead to morbidity and mortality. To prevent this from happening, parents can be educated on proper nutrition and the importance of breastfeeding infants to ensure they receive all the nutrients they need.A diet rich in carbohydrates, fats that make up 10% of the total caloric needs, and proteins that make up 15% of the caloric needs can prevent kwashiorkor.
Proteins can be found in the following foods

Seafood
Peas
Nuts
Seeds
Eggs
Lean meat
Beans

Treatment
WHO guidelines outline 10 general principles for the inpatient management of severely malnourished children.
Treat/prevent hypoglycemia
Treat/prevent hypothermia
Treat/prevent dehydration
Correct electrolyte imbalance
Treat/prevent infection
Correct micronutrient deficiencies
Start cautious feeding
Achieve catch-up growth
Provide sensory stimulation and emotional support
Prepare for follow-up after recoveryBoth clinical subtypes of severe acute malnutrition (kwashiorkor and marasmus) are treated similarly. Upon initial treatment, children with kwashiorkor may experience weight loss as their edema resolves. Therefore, after concerns of refeeding syndrome have passed, children may require 120-140% of their estimated caloric needs in order to achieve catch-up growth.The cause, type, and severity of malnutrition determines what type of treatment would be most appropriate. For primary acute malnutrition, children with no complications are treated at home and are encouraged to either continue breastfeeding (for infants) or start using ready-to-use therapeutic foods (for children). For secondary acute malnutrition, the underlying cause needs to be identified to appropriately treat children. Only after the primary disease is determined can an appropriate dietary plan be made, as fluid, vitamins, and macronutrients may need to be considered to not exacerbate the cause of the malnutrition.Ready-to-use therapeutic foods (RUTFs) and F-75 and F-100 milks were created to provide appropriate nutrition and caloric intake to those experiencing malnutrition. F-75 milk would be ideal when trying to reintroduce food into a malnourished person, and F-100 milk would be used to aid in weight gain. While RUTFs and F-100 milk were made to have the same nutritional value, RUTFs are beneficial as they are dehydrated and do not require much preparation.

Prognosis
Kwashiorkor is associated with a high risk of mortality and long-term complications. Treatment under the guidelines of the World Health Organization has proven to reduce this mortality risk and affected children tend to recover faster than children with other severe malnutrition diseases. However, physical and intellectual capabilities are not fully restored. Growth stunting and chronic disruption of microbiota are commonly observed after recovery.A high risk of death is identified by a brachial perimeter < 11 cm or by a weight-for-age threshold < −3 z-scores below the median of the WHO child growth standards. In practice, malnourished children with edema are suffering from potentially life-threatening severe malnutrition.

Epidemiology
Kwashiorkor is rare in high income countries. It is mostly observed in low-income and middle income nations and regions such as Southeast Asia, Central America, Congo, Ethiopia, Puerto Rico, Jamaica, South Africa, and Uganda, where poverty is prominent. Occurrences of severe malnutrition also tend to trend higher under conditions of food insecurity, higher prevalence of infectious diseases, lack of access to appropriate care, and poor living situations with inadequate sanitation. Communities experiencing famine are affected the most especially during the rainy season. Prevalence varies, but it affects children of either sex commonly under five years old. "Globally, kwashiorkor indirected accounted for 53% of deaths among children under five between 2000 and 2003 when associated with other common childhood diseases like acute respiratory infections, malaria, measles, HIV/AIDS and other causes of perinatal deaths."When compared to marasmus in developing countries, kwashiorkor has a lower prevalence, "0.2%-1.6% for kwashiorkor and 1.2%-6.8% for marasmus." Factors such as "diet, geographical locations, climate and aflatoxin exposure" are associated with the difference in prevalence for kwashiorkor and marasmus.

History
It is likely that kwashiorkor was commonly seen around the world long before 1933, when Cicely Williams published research which took the Ga name for the disease. There were already many names for the illness which referenced the cessation of breastfeeding, or the consumption of diets which were too high in starch. However, Williams was the first to suggest that this might be a deficiency of protein.   Despite publishing in 1933, it was only in 1949 that the World Health Organization officially recognized kwashiorkor as a public health concern. This period also correlated with the promotion of infant formula, often by European colonial powers. The substitution of breastmilk for formula contributed significantly to the increasing visibility of kwashiorkor throughout the twentieth century. Cicely Williams later described the promotion of formula as "the most criminal form of sedition, and that those deaths should be regarded as murder." These arguments underpinned the 1970s Nestlé boycott.

Effects on pharmacokinetics
Those experiencing poverty-related infectious diseases (PRDs) such as malaria and tuberculosis are also likely to be malnourished. Malnutrition can affect the pharmacokinetics of various drugs used to treat PRDs by changing a drugs bioavailability, distribution, and elimination. To optimize treatment of those diseases, there needs to be more research into how severe malnutrition, specifically kwashiorkor, can affect treatment response.

Research directions
Current research and recommendations to manage severe acute malnutrition (SAM), such as kwashiorkor, in children are largely based on expert opinions. Only one-third of the WHO guidelines for management of SAM are based on epidemiological and clinical research. Further studies are needed in order to "improve treatment outcomes in the large number of children with SAM."

See also
Anemia
Emaciation
Starvation
Marasmus
Protein poisoning

References
External links
Picot, J; Hartwell, D; Harris, P; Mendes, D; Clegg, A J; Takeda, A (2012). "The effectiveness of interventions to treat severe acute malnutrition in young children: a systematic review". Health Technology Assessment. 16 (19). doi:10.3310/hta16190. PMC 4781582. PMID 22480797. NBK98566.
 Media related to Kwashiorkor at Wikimedia Commons