Excerpt from Marasmus

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Background

Marasmus is 1 of the 3 forms of serious protein-energy malnutrition (PEM). The other 2 are kwashiorkor (KW) and marasmic KW. These forms of serious PEM represent a group of pathologic conditions associated with a nutritional and energy deficit occurring mainly in young children from developing countries at the time of weaning. They are frequently associated with infections, mainly gastrointestinal infections. The reasons for a progression of nutritional deficit into marasmus rather than KW are unclear and cannot be solely explained by the composition of the deficient diet (ie, a diet deficient in energy for marasmus and a diet deficient in protein for KW). The study of these phenomena is considerably limited by the lack of an appropriate animal model.

Marasmus is a serious worldwide problem that involves more than 50 million children younger than 5 years. According to the World Health Organization (WHO), 49% of the 10.4 million deaths occurring in children younger than 5 years in developing countries are associated with PEM. Malnutrition has been a permanent priority of the WHO for decades. Although PEM occurs more frequently in low-income countries, numerous children from higher-income countries are also affected, including children from large urban areas and of low socioeconomic status, children with chronic disease, and children who are institutionalized.

Hospitalized children are also at risk for PEM when they experience complex conditions, such as oncologic disease, genetic disease, or neurological disease, requiring prolonged and complicated hospital care. In these conditions, the challenging nutritional management is often overlooked and insufficient, resulting in an impairment of the chances for recovery and the worsening of an already precarious neurodevelopmental situation. PEM results in not only high mortality (even for hospitalized children, without any improvement during the last 2 decades) but also morbidity and suboptimal neurological development. The social and economic implications of PEM and its complications are incalculable.

This review is limited to marasmus resulting from an insufficient nutritional intake as observed under impaired socioeconomic conditions, such as those present in developing countries. This condition is most frequently associated with acute conditions (eg, gastroenteritis) or chronic conditions (eg, tuberculosis, HIV infection).

Pathophysiology

Various extensive reviews of the pathophysiological processes resulting in marasmus exist. Unlike KW, marasmus can be considered as an adaptation to an insufficient energy intake. Marasmus results from a negative energy balance. This imbalance can result from a decreased energy intake, increased energy expenditure, or both, such as that observed in acute or chronic disease. Children adapt to an energy deficit with a decrease in physical activity, lethargy, a decrease in basal energy metabolism, slowing of growth, and finally weight loss.

Pathophysiological changes associated with nutritional and energy deficits can be described as (1) body composition changes, (2) metabolic changes, and (3) anatomic changes.

Body composition

Body mass: Body mass is significantly decreased in a heterogeneous way.

Fat mass: Fat stores can decrease to as low as 5% of the total body weight and be macroscopically undetectable. The remaining fat is usually stored in the liver, as is often observed in KW but also to a lesser extent in marasmus.

Total body water: The proportion of water content in the body increases with the increased seriousness of PEM (marasmus or KW) and is associated with the loss of fat mass, which is poor in water. The proportion of extracellular water also increases, often resulting in edema. Edema is significant in KW but can also be present in marasmus or in the frequently encountered mixed forms of PEM. The increase in extracellular water is proportional to the increase in the total body water. During the first days of therapy, part of the extracellular water shifts to the intracellular compartment and part of it is lost in the urine, resulting in the observed initial weight loss with treatment.

Protein mass: Mainly represented by muscle and some organs (eg, heart), protein mass can decrease up to 30% in the most serious forms. The muscle fibers are thin with loss of striation. Muscle cells are atrophic, and muscle tissue is infiltrated with fat and fibrous tissue. Total recovery is long, but it seems possible.

Other organ mass: The brain, skeleton, and kidney are preserved, whereas the liver, heart, pancreas, and digestive tract are first affected.

Pediatric and adult physiologic change: Finally, physiologic changes are different in infants and children when compared to adults. For example, marasmic infants have an increased tendency to hypothermia and hypoglycemia, requiring the frequent administration of small meals. This can be explained by the body composition imbalance of marasmic children in favor of high–energy-consuming organs, such as brain and kidney, as compared to energy storage organs, such as muscle and fat.

Assessment of fat and muscle mass: As described below, assessment of the fat and muscle mass loss can be performed clinically by measuring arm circumference (see Image 1) or skinfold thickness, such as triceps skinfold. The diagram illustrates the validity of this assessment method. Because arm circumference is relatively constant in healthy children aged 1-5 years, it roughly represents a general assessment of nutritional status.

Minerals and vitamins

Potassium: Potassium is the electrolyte most studied in marasmus. Total body potassium deficit is associated with decreased muscle mass, poor intake, and digestive losses. This potassium deficit, which can reach 15 mEq/kg, contributes to hypotonia, apathy, and impaired cardiac function.

Other electrolytes: Plasma sodium concentration is generally within the reference range, but it can be low, which is then a sign of a poor prognosis. However, intracellular sodium level is elevated in the brain, muscle, and red and white blood cells, explaining the sodium excretion in the first days of recovery.

Other minerals: A deficit in calcium, phosphorus, and magnesium stores also exists. Iron deficiency anemia is consistently observed in marasmus. However, in the most serious forms, iron accumulates in the liver, most likely because of the deficit in transport protein. These patients are at higher risk of mortality; therefore, iron is supplemented only after the acute recovery phase is completed. Zinc, selenium, and magnesium are more significantly reduced in KW but are also constantly deficient in marasmus. Several studies have shown improved recovery from malnutrition and decreased mortality with supplementation of these 3 micronutrients.

Vitamins: Both fat-soluble vitamins (ie, A, D, E, K) and water-soluble vitamins (eg, B-6, B-12, folic acid) must be systematically administered. Vitamin A is essential to retinal function, has a trophic effect on epithelial tissues, and plays a major role as an antioxidant agent. Vitamin A deficit affects visual function (eg, conjunctivitis, corneal ulcer, night blindness, total blindness) and digestive, respiratory, and urinary functions. Furthermore, vitamin A supplementation programs have resulted in decreased mortality and morbidity, in particular, during diarrheal disease and measles.

Vitamin and micronutrient deficiencies can be differentiated in 2 categories listed below. Patients with deficiencies of type 1 nutrients present with late and specific clinical signs. In contrast, patients with deficiencies of type 2 nutrients are difficult to identify because blood levels are unreliable and the clinical signs are nonspecific, such as the growth retardation with mild deficiency and weight loss with significant deficiency. Furthermore, type 2 nutrient deficiencies are often combined. Therefore, these deficiencies are global and require a global nutritional rehabilitation, such as WHO standardized solution.

Below are characteristics of type 1 and type 2 deficiencies, according to Golden from a 1991 report.

• Type 1 deficiencies
• • Specific clinical signs
  • Clinical signs appear after a latency period
  • Used in specific metabolic pathways
  • Are independent of one another
  • Variable tissue concentration
• Type 2 deficiencies
• • Nonspecific clinical signs
  • Nutrient status related to daily intake
  • Used in a variety of organs and metabolic pathways
  • Nutrient interaction
  • Constant tissue concentration

Below are lists of nutrient classification according to the clinical response to deficiency in type 1, with reduction of tissue concentration, and type 2 with growth deficit.

• Type 1 nutrients
  • Selenium
  • Iodine
  • Iron
  • Copper
  • Calcium
  • Manganese
  • Thiamin
  • Riboflavin
  • Ascorbic acid
  • Retinol
  • Tocopherol
  • Calciferol
  • Folic acid
  • B-12 vitamin
  • Pyridoxine
• Type 2 nutrients
• • Sodium
  • Sulfur
  • Essential amino acids
  • Potassium
  • Sodium
  • Magnesium
  • Zinc
  • Phosphorus
  • Water

Metabolic changes

Energy metabolism: With reduced energy intake, a decrease in physical activity occurs along with a slower and, ultimately, lack of growth. Weight loss first occurs by a decrease in fat mass, then a decrease in muscle mass, as clinically measured by changes in arm circumference (see Image 1). Muscle mass loss results in a decrease of energy expenditure. Reduced energy metabolism can impair the response of patients with marasmus to changes in environmental temperature, resulting in an increased risk of hypothermia. Furthermore, during infection, fever is reduced compared to a well-nourished patient. In case of nutrient deficiency, the metabolism is redirected to vital function (requiring 80-100 kcal/kg/d). During recovery, the energy cost of catch-up growth has to be added (up to 100 kcal/kg/d). At this stage, energy needs can be massive.

Protein metabolism: Intestinal absorption of amino acids is maintained, despite the atrophy of the intestinal mucosa. Protein turnover is decreased (up to 40% in severe forms), and protein-sparing mechanisms regulated by complex hormonal controls redirect amino acids to vital organs. Amino acids liberated from the loss of muscle mass are recycled in priority by the liver for the synthesis of essential protein. Total plasma proteins, including albumin, are decreased, whereas gamma globulins are often increased by the associated infections.

Albumin: An albumin concentration lower than 30 g/L is often considered as the threshold below which edema develops from decreased oncotic pressure. However, in marasmus, albumin concentration can occasionally be below this value without edema. Prealbumin concentration is a sensitive index of protein synthesis. It decreases with decreased protein intake and rapidly increases in a few days with appropriate nutritional rehabilitation. Insulinlike growth factor 1 (IGF-1) is another sensitive marker of nutritional status.

Carbohydrate metabolism: This has mainly been studied in order to explain the serious and often fatal hypoglycemia occurring in the initial renutrition phase of marasmic children. Glucose level is often low initially, and the glycogen stores are depleted. Also, a certain degree of glucose intolerance of unclear etiology exists, possibly associated with a peripheral resistance to insulin or with hypokalemia. In the initiation of renutrition or in association with diarrhea or infection, a significant risk of profound and even fatal hypoglycemia occurs. Small and frequent meals are recommended, including during the night, to avoid death in the early morning. Furthermore, the digestion of starch is impaired by the decreased production of amylase by the pancreas. Lactose malabsorption is frequent but is generally without clinical consequences. In most cases, renutrition using milk is possible.

Fat metabolism: Dietary fats are often malabsorbed in the initial phase of marasmus renutrition. The mobilization of fat stores for energy metabolism takes place under hormonal control by adrenaline and growth hormone. Blood lipid levels are usually low, and serious dysregulation of lipid metabolism can occur, mainly during KW and rarely during marasmus.

Anatomic changes

Digestive tract

The entire digestive tract from mouth to rectum is affected. The mucosal surface is smooth and thin, and secretory functions are impaired. The decrease in gastric hydrochloric acid (HCl) excretion results in bacterial overgrowth in the duodenum. The peristalsis is slow. Proportionally, the digestive tract is the organ system that loses the largest mass during marasmus. However, these important alterations of the digestive tract interfere only moderately with normal nutrient absorption. Therefore, early enteral renutrition is not contraindicated but is encouraged because some of the nutrients necessary for the recovery of the intestinal mucosa are used directly from the lumen.

In addition to the anatomic changes associated with PEM, the frequent intestinal infections by viruses, bacteria, and toxins also contribute to the changes in the digestive tract. Liver volume usually decreases, as do other organ volumes. An enlarged liver suggests the possibility of other diagnoses, such as KW or hepatitis. Liver synthesis function is usually preserved, although protein synthesis is decreased, as reflected by the decreased albumin and prealbumin levels. The neoglycogenesis is decreased, further increasing the risk for hypoglycemia. The detoxifying function of the liver is impaired with structural changes in the liver cells. Therefore, drugs that are metabolized by the liver should be administered with caution, and liver function should be monitored.

Endocrine system

The main perturbations are observed in the thyroid, insulin, and growth hormone system. As in any stressed state, the adrenergic response is activated (see Image 2). This response is functional in marasmus but less so in KW. Muscle proteins are converted into amino acids, used for the hepatic synthesis of lipoproteins. These lipoproteins contribute to the mobilization of triglycerides from the liver. In contrast, during KW, this function is impaired, resulting in liver steatosis, which is not usually present in marasmus. However, any precipitating factor, such as gastroenteritis or inappropriate renutrition, can disrupt this fragile adaptive mechanism.

Furthermore, in serious marasmus, a significant degree of hypothyroidism, with a decrease in the size of the thyroid gland and repercussions on the brain function and psychomotor development exists. In less severe forms, the impaired thyroid function has fewer clinical consequences. Insulin levels are low and contribute to a certain degree of glucose intolerance, especially during KW. Therefore, high-carbohydrate diets are inappropriate. Growth hormone levels are initially within the reference range, but they progressively decrease with time, explaining the halt in linear growth observed with marasmus. After initiation of renutrition, the substantial anabolism results in a rapid linear growth spurt.

Hematopoietic system

A moderate normochromic or slightly hypochromic anemia is usually present, with normal red blood cell size. Iron and folate deficiencies, intestinal parasites, malaria, and other chronic infections exacerbate the anemia. However, iron stores are present in the liver. Therefore, iron supplementation should not be initially implemented. Oral iron is poorly tolerated by the digestive tract. The other blood cells (eg, thrombocytes, white blood cells) are also affected, but with generally limited clinical consequences. Blood clotting mechanisms are usually preserved, except in the case of serious vitamin K deficiency.

Immune system

Immune impairment and infections are usually associated with marasmus. Thymus atrophy is a characteristic manifestation of marasmus, but all T lymphocyte–producing tissues are affected. However, B-lymphocyte tissues, such as Peyeri plaques, the spleen, and the tonsils, are relatively preserved. Cellular immunity is most affected, with a characteristic tuberculin anergy. However, antibody production is maintained. In marasmus, a general acquired immunodeficiency occurs, with a decrease in secretory immunoglobulin A (IgA) and an impairment of the nonspecific local defense system, such as mucosal integrity and lymphokine production. Bacteriemia, candidiasis, and Pneumocystis carinii infection are frequently present. Immune impairment is less frequent with moderate malnutrition. Immunological recovery is generally rapid, except if measles is associated.

Brain and nervous system

Cerebral tissue is usually preserved during marasmus. Brain atrophy with impairment of cerebral functions is only present in severe forms of marasmus. Effects on the brain are more important if malnutrition takes place during the first year of life or during fetal life. Irritability and apathy are characteristic of marasmus, but they improve rapidly with recovery. The permanent developmental consequences of marasmus are difficult to evaluate, but several ongoing studies are evaluating these long-term consequences as well as the benefit of nutritional supplementation with various vitamins and minerals.

Cardiovascular system

Cardiac muscle fiber is thin, and the contractility of the myofibrils is impaired. Cardiac output, especially systolic function, is decreased in the same proportion as the weight loss. Bradycardia and hypotension commonly occur in severe forms of malnutrition. Electrolyte imbalances present during marasmus modify the ECG findings. With this impaired cardiac function, any increase of intravascular volume during rehydration or blood transfusion can result in a significant cardiac insufficiency. With the rapid metabolic, energy, and electrolyte changes of the initial phase of renutrition, this period is also a period of high risk for arrhythmia or cardiac arrest. Therefore, close clinical monitoring is critical in children with circulatory compromise.

Frequency

United States

Marasmus is relatively infrequent in children. In 1995, 228 deaths were attributed to marasmus in the United States. Most of these deaths were in elderly adults, and only 3 occurred in children. However, these data do not include deaths associated with marasmus complicating anorexia nervosa. Incidence of nonfatal marasmus is unclear in the United States because most patients have an underlying condition, and marasmus is not reported as an admission or discharge diagnosis. However, several reports of PEM in hospitalized children exist, suggesting that the diagnosis of marasmus may be underreported in the United States.

International

Nearly 30% of humans currently experience one or more of the multiple forms of malnutrition. Close to 50 million children younger than 5 years have PEM, and half of the children who die younger than 5 years are undernourished (see Image 3).

At the same time, a massive global epidemic of obesity, especially in countries in rapid economic transition, is emerging in children and adolescents.

Mortality/Morbidity

Six million children younger than 5 years die every year of malnutrition. Approximately 70 million present with wasting, and 230 million present with some stunting. Fifty percent of the children in Asia are malnourished, 30% are malnourished in Africa, and 20% are malnourished in Latin America.

Race

No racial predilection exists in the prevalence of malnutrition, but a strong association exists with the geographic distribution of poverty.

Sex

No sexual predilection exists, although, in some parts of the world, cultural practices place girls at a disadvantage for PEM.

Age

Marasmus is more frequent in children younger than 5 years because this period is characterized by increased energy needs and increased susceptibility to viral and bacterial infections. Weaning, which occurs during this period, is often complicated by factors such as geography (eg, drought, poor soil productivity), economy (eg, illiteracy, unemployment), hygiene (eg, access to quality water), public health (eg, number of nurses is more than number of physicians), and culture and dietetics (eg, intrafamily distribution of high-nutrition foods).

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