Malnutriția ca patologie multifactorială: mecanisme fiziopatogenice și corelații clinice

Nutritional status is a key indicator of overall health. Malnutrition is a pathological condition that arises when the body does not adequately utilize calories or nutrients to support normal physiological functions and growth. It may result either from an excess of caloric intake due to an underlying condition or disease, from a deficiency of specific nutrients in the diet, or from a combination of both⁽¹⁾. This represents a significant public health issue in developing countries, and affects the entire community. However, infants and young children are the most vulnerable, due to their high nutritional requirements for growth and development. This medical condition occurs from an inadequate, insufficient or unbalanced diet, as well as from unhealthy dietary choices⁽²⁾.

According to the Global Burden of Disease study from 2015, protein-energy malnutrition (PEM) was responsible for 174,000 deaths among children under 5 years old. The risk of mortality is significantly increased by hunger, particularly in cases of severe malnutrition. The Lancet Nutrition Series, published in 2013, estimated that 875,000 deaths were attributable to wasting, accounting for 12.6% of deaths in children under 5 years of age. Additionally, 516,000 deaths were caused by severe wasting, representing 7.4% of under-5 child mortality. All forms of stunting, wasting and underweight have been associated with an increased risk of death, according to a pooled analysis of ten longitudinal studies, which followed 54,000 child-years and documented 1300 deaths among children under 5 years old^(3,4).

The American Society for Parenteral and Enteral Nutrition defines malnutrition as “an imbalance between nutrient requirements and intake, which can adversely affect growth, development, and other relevant outcomes due to deficiencies in energy, protein or micronutrients”. Malnutrition encompasses undernutrition (wasting, stunting, underweight), vitamin and mineral deficiencies, overweight and obesity, as well as diet-related noncommunicable diseases. Undernutrition in childhood remains a major public health concern in many middle-income countries⁽⁵⁾.

Each year, between 8 and 11 million children under the age of 5 years old lose their lives, with malnutrition being a major contributing factor in over 35% of these tragic deaths. What is particularly concerning is that many of these deaths could be prevented through simple interventions, such as promoting economic growth and implementing effective public health policies. Although the situation varies by region, there is a sign of hope: globally, the number of cases of protein-energy malnutrition (PEM) among children is declining. This positive trend is especially evident in Asia; however, in Africa, the situation is deteriorating, with an increasing number of children affected by PEM⁽⁴⁾.

Recently, member states of the World Health Organization (WHO) have ratified a commitment to nine global nutrition targets to be achieved by 2025. These include a 40% reduction in childhood stunting, reducing the prevalence of acute malnutrition in children to below 5%, ensuring that the number of overweight children does not increase, and the elimination of all forms of malnutrition by 2030⁽⁶⁾.

Malnutrition affects approximately one-third of children in developing countries. Its primary causes include poverty, international conflicts, illiteracy, crises and limited access to healthcare services⁽¹⁾. Child malnutrition is positively correlated with the socioeconomic status of parents and negatively correlated with their level of education. This is primarily due to low household income, which often results in inadequate nutrition. In some cases, there is a physical lack of sufficient, hygienic, healthy and socially acceptable food⁽⁷⁾. Children between 6 and 24 months of age are typically affected by protein-energy malnutrition, which is often associated with protein-deficient meals, early weaning, and various illnesses⁽¹⁾.

According to the study conducted by Obasohan et al., girls have significantly lower odds of being malnourished compared to boys. Children aged 24 to 35 months have 2.22 times higher odds of developing malnutrition than those aged 6 to 11 months. Low birth size increases the risk of malnutrition, with children born small or average size having higher odds of malnutrition compared to those born large. Anemic children and those who have experienced diarrhea are more prone to malnutrition. Additionally, children of working-class mothers have higher odds of being malnourished than those of non-working mothers. The results also show that the wealthier the household, the less likely children are to be malnourished compared to those from the poorest households⁽⁶⁾.

Nutritional status assessment can be conducted using biochemical indicators, anthropometry and clinical manifestations of malnutrition. The interpretation of anthropometric data, such as height and weight, provides an objective and quantitative aspect of nutritional evaluation. Anthropometry is superior to other nutritional indicators because body measurements are sensitive to the entire spectrum of malnutrition, whereas biochemical and clinical indicators are useful only in the most extreme circumstances^(8,9).

Malnutrition is a well-known complication associated with chronic liver disease (CLD), affecting 60-80% of children in the advanced stages of the disease. It is estimated that in low- and middle-income countries (LMICs), 250 million children under 5 years of age (43%) do not reach their full developmental potential. Adequate nutrition, especially during the first 1000 days, can have a direct impact on early development by influencing brain growth, as well as an indirect impact by reducing disease burden, promoting growth and improving the child’s interactions with the surrounding environment^(10,11).

The case-control study conducted by Dutta et al. classified patients as follows: severe malnutrition was defined as malnutrition below 60% of the expected value, while mild-to-moderate malnutrition was defined as 60% to 80% of the 50^th percentile weight-for-age. Stunting, or chronic malnutrition, was considered when the height-for-age ratio was less than 90% of the predicted value, with a normal weight-for-height ratio⁽¹⁾.

Acute malnutrition caused by a deficiency of protein and calories is known as protein-energy malnutrition (PEM). This includes conditions such as kwashiorkor and marasmus. Acute malnutrition is indicated by low weight relative to height. Marasmus and kwashiorkor are the main forms of severe acute malnutrition⁽¹²⁾.

A study conducted by Amoah et al. revealed that, among 245 participating children, moderate underweight was more prevalent in girls (35.8%) than in boys (18.1%). Severe stunting was more frequently observed in boys (8.4%) compared to girls (3.1%), while moderate stunting was more common among girls (11.1%) than boys (4.8%). Regarding acute malnutrition (wasting), the distribution between boys and girls was similar. Acute malnutrition was less frequent in children aged 11 to 23 months, with 1.2% moderately malnourished and 3.6% severely malnourished. In contrast, among children aged 24 to 35 months, moderate and severe malnutrition rates were 42.6% and 5.7%, respectively; for those aged 36 to 47 months, the rates were 33.3% and 20%. In children aged 48 to 59 months, moderate and severe malnutrition rates were 33.3% and 11.1%, respectively⁽¹³⁾.

Types of protein-energy malnutrition

Marasmus

In children, protein-energy malnutrition occurs as a result of insufficient protein and energy intake. Marasmus, one of the two main extreme forms of protein-energy malnutrition, results from calorie and energy deficiency, particularly in children under 5 years old⁽¹⁴⁾.

According to WHO, severe acute malnutrition (SAM) is classified as non-edematous (marasmus) when weight-for-height is below -3 Z-scores (WHZ) compared to the WHO growth standards median, or when the mid-upper arm circumference (MUAC) is less than 115 mm in children aged 6 to 59 months old. SAM is classified as edematous (kwashiorkor) when bilateral pitting edema is present⁽¹⁵⁾.

The nutritional status of the host directly influences immune modulation and susceptibility to infectious and parasitic diseases. The presence of these infections can impair the host’s ability to absorb nutrients, thereby leading to malnutrition and creating a self-perpetuating cycle. Leishmaniasis, a group of neglected tropical diseases caused by protozoan parasites of the genus Leishmania, leads to a decline in physical strength, making individuals, especially children, highly vulnerable to infections. Patients with compromised nutritional status exhibit a reduced response to therapy, highlighting the need for comprehensive treatment approaches that address both the disease and nutritional deficiencies. Moreover, the critical role of the host’s nutritional status in influencing treatment efficacy suggests that malnutrition exacerbates infection severity and impairs immune responses essential for recovery. Therefore, there exists a vicious cycle between malnutrition and infection: infections can cause loss of appetite, indirectly leading to inadequate food intake, which in turn worsens nutritional status and increases individuals’ susceptibility to subsequent infections⁽¹⁶⁾.

Kwashiorkor

Kwashiorkor is an extreme form of protein-energy malnutrition that primarily occurs in infants and young children consuming a diet deficient in protein but with relatively normal caloric intake. Children with kwashiorkor are characterized by edema, abdominal distension, hepatomegaly, dermatitis and hypopigmented hair. Low protein intake leads to reduced serum albumin and ferritin levels, causing hypoalbuminemia and anemia, respectively. Hypoalbuminemia decreases oncotic pressure, resulting in edema, which also occurs in adult patients with heart failure due to low protein intake similar to children; however, other mechanisms are involved as well. Previous studies have reported that inflammation (indicated by elevated C-reactive protein levels), along with lower levels of lymphocytes, hemoglobin, sodium and total cholesterol, are associated with hypoalbuminemia in heart failure patients. Body Mass Index (BMI) is not a determining factor for hypoalbuminemia. Higher levels of BNP have also been independently associated with kwashiorkor-type malnutrition⁽¹⁷⁾.

Moderate acute malnutrition (MAM) in children aged 6 to 59 months old was diagnosed either based on a weight-for-height index between -3 and -2 Z-scores compared to the median of the WHO Child Growth Standards, or based on a mid-upper arm circumference (MUAC) measurement between 115 mm and 125 mm, as assessed by the evaluating physician⁽¹⁸⁾.

Characterized by a significant deficit in the weight-for-height ratio, bilateral pitting edema, or a mid-upper arm circumference (MUAC) below a specific threshold, severe acute malnutrition (SAM) poses considerable risks to the health and development of children⁽¹⁹⁾. In a study conducted by Gonzales et al., based on the revised Starling model, it was observed that fluid filtered from the interstitial space is primarily drained back into circulation as lymph. The researchers measured extracellular matrix (ECM) proteins found in the lymphatic system. Podoplanin, a mucin-like glycoprotein present in the alveoli, heart and lymphatic vascular system, was negatively associated, whereas the hyaluronic acid receptor 1 (LYVE1) on lymphatic vessel endothelium was positively associated with kwashiorkor. Plasma levels of LYVE1 also decreased during nutritional rehabilitation in both kwashiorkor and marasmus phenotypes, while podoplanin levels remained unchanged⁽²⁰⁾. Lymphatic drainage is an active, energy-dependent process involving the mechanical pumping of fluid by lymphatic valves. It remains unclear why lymphatic drainage is specifically impaired in kwashiorkor, but evidence that markers of lymphatic function may be associated with edema provides an important new insight into edema formation⁽²¹⁾.

Although extracellular matrix (ECM) remodeling is typically triggered by inflammation, analysis of plasma markers of systemic inflammation revealed no significant differences between kwashiorkor and marasmus when cases were matched for serum albumin levels. This suggests that ECM degradation in kwashiorkor is driven by mechanisms independent of the inflammatory response. Therefore, increased ECM degradation represents an albumin-independent mechanism contributing to edema formation in severe malnutrition. Children with kwashiorkor may be predisposed to greater ECM degradation compared to those with marasmus when exposed to the same level of inflammatory insult⁽²⁰⁾.

LYVE1 and podoplanin are both markers of lymphatic endothelial integrity, predominantly expressed in lymphatic vessels. LYVE1 and podoplanin are essential for lymphatic system development, and ablation of podoplanin and LYVE1 in transgenic mice has resulted in reduced lymphatic transport and lymphedema. Differential plasma levels of these markers suggest that the lymphatic system may be compromised in kwashiorkor, leading to inefficient lymphatic fluid drainage⁽²²⁾.

Marasmic kwashiorkor

This clinical manifestation is characterized by a combination of features specific to two types of malnutrition⁽²³⁾. Kwashiorkor involves edema and affects the skin, hair and liver, whereas marasmus is characterized by severe weight loss, muscle atrophy, absence of edema and a low weight-for-height ratio^(24,25). Protein-energy malnutrition (PEM) induces significant physiological and functional alterations affecting a wide range of body systems. These changes include alterations in body composition, dysfunctions of the gastrointestinal tract, liver and kidneys, as well as modifications in tissue protein levels, body fluids, plasma and hormonal regulation. The impact of PEM is systemic, influencing fundamental physiological processes essential for maintaining health and supporting the organism’s growth and development⁽²³⁾.

Impact of protein-energy malnutrition

The study conducted by Chama et al. included 322 participants, representing children aged 6 to 24 months old, with 240 boys, most of them being from urban areas. Forty-four (10.3%) participants were diagnosed with tuberculosis (TB), the majority presenting with pulmonary TB. Among the participants, the most common comorbidities observed were sickle cell disease, followed by acute watery diarrhea, anemia, pneumonia and acute pharyngotonsillitis. Of the cases, 116 (64.4%) were diagnosed with severe acute malnutrition (SAM), while 64 cases (35.6%) presented with moderate acute malnutrition (MAM). The majority (56%) of children had a weight-for-height Z-score between -2 and +2. Hematological parameters revealed a mean platelet count of 351, a mean neutrophil count of 5, a mean lymphocyte count of 4, a mean monocyte count of 0.8, a mean hemoglobin level of 10.3, and a mean white blood cell count of 9.5⁽¹⁸⁾.

The strong and synergistic relationship between malnutrition and infection is well recognized, with significantly higher mortality rates observed in malnourished children compared to their healthy counterparts. A recent study involving a substantial number of hospitalized Gambian children clearly demonstrated the link between increased mortality rates associated with various viral respiratory illnesses and malnutrition, characterized by a low weight-for-age ratio⁽²⁶⁾.

Mycobacterium tuberculosis, the most common infectious disease-causing death worldwide, infects one-third of the global population. In developing countries, where protein-energy malnutrition is also prevalent, this infection is significantly influenced by malnutrition, and represents a leading cause of morbidity and mortality. Experimental model results highlight the importance of malnutrition as a major risk factor for tuberculosis. Additionally, undernutrition can adversely affect the clinical outcomes of tuberculosis⁽²⁷⁾. A recent meta-study revealed a link between an increased risk of active tuberculosis and low serum levels of vitamin D⁽²⁸⁾. It is essential to emphasize that tuberculosis is a common disease whose course, marked by ongoing inflammatory processes, worsens malnutrition and leads to classic cachexia. IgG1 antibodies have been partially implicated in this, as they increase the levels of proinflammatory cytokines (IFN-g and IL-6) but not the anti-inflammatory cytokines (IL-10). HIV coinfection and inadequate treatment regimens have been the main causes for the rise of extensively drug-resistant strains of Mycobacterium tuberculosis. It has been proposed that malnutrition has played a role in the increase of drug-resistant M. tuberculosis strains⁽²⁷⁾.

Complications

In protein malnutrition (PMN), anemia, increased red cell distribution width (RDW) and low serum albumin (ALB) levels are common findings. PMN disrupts albumin synthesis due to hepatic RNA loss and polysome disaggregation, leading to hypoalbuminemia, particularly in kwashiorkor. Elevated levels of liver enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) indicate hepatic injury, while increased alkaline phosphatase (ALP) levels are associated with impaired bone development and liver dysfunction. Moreover, PMN impairs fatty acid oxidation, resulting in enhanced lipogenesis and triglyceride (TG) accumulation in the liver. Triglyceride levels are reduced in kwashiorkor but are normal or elevated in marasmus. These alterations underscore the metabolic and organ dysfunctions characteristic of protein malnutrition⁽²³⁾.

Malnutrition has been associated with allergic disorders in children, which are mediated by Th2 immune responses⁽²⁷⁾.

In the cohort studied by Singha et al., pneumonia was identified as the predominant complication, afflicting 54.55% of individuals. Anemia also had a significant prevalence, impacting 58.06% of the children. Urinary tract infections (UTIs) were observed in 9.67% of ca­ses, while tuberculosis was diagnosed in three children (4.83%). Developmental delay was noted in 3.22% of the children, and sepsis was detected in 12.58%. Acute gastroenteritis developed in 18.18% of the children. The average length of hospital stay was 14 days⁽²⁹⁾.

Another significant complication in undernourished children is sepsis. Sepsis involves a systemic inflammatory response characterized by humoral and cellular reactions, as well as proinflammatory and anti-inflammatory mechanisms, leading to microcirculatory damage and endothelial dysfunction. Hormonal alterations are associated with increased cyclic adenosine monophosphate (cAMP) levels in lymphoid cells, resulting in stress-induced immune dysfunction. A key feature of the metabolic disturbances in sepsis is the combination of an increased demand for substrates to support the high energy costs and enhanced tissue tolerance. Nutritional management of the hypermetabolic-hypercatabolic syndrome in critically ill children remains a complex challenge, extensively discussed in multicenter reviews. This syndrome plays a central role in the development of sepsis-induced organ dysfunction, and it is characterized by a marked elevation in metabolic rate, increased oxygen consumption, excessive CO₂ production and a negative nitrogen balance⁽³⁰⁾.

The main recommendations of the Surviving Sepsis Campaign (SSC) 2012 regarding nutritional therapy for sepsis/septic shock are as follows. The updated SSC 2021 guidelines do not include significant changes in nutritional support for sepsis:

1. Oral or enteral nutrition (EN) is preferred, if well tolerated, over full glucose or intravenous feeding during the first 48 hours after sepsis/septic shock diagnosis (Grade 2C).

2. Initiate feeding with small volumes and gradually increase as tolerated (Grade 2B).

3. The use of intravenous glucose combined with EN during the first week following sepsis/septic shock diagnosis is preferred over total parenteral nutrition (TPN) or mixed parenteral-enteral nutrition (Grade 2B).

4. Therapeutic nutrition without immu­no­modulatory supplements is preferred over the use of such sup­ple­ments⁽³¹⁾.

However, as part of the Stop Sepsis campaign (2020), an analysis of international guidelines for the management of sepsis-associated organ dysfunction in children yielded several recommendations. These include avoiding the administration of selenium, glutamine, arginine and zinc in children with septic shock or sepsis-induced multiple organ dysfunction syndrome. Additionally, the use of specialized lipid emulsions is discouraged in children with septic shock or sepsis-related organ dysfunction. Notably, there are no specific recommendations regarding the use of early hypocaloric or trophic enteral nutrition followed by a gradual transition to full enteral nutrition compared to early full enteral nutrition in children with severe sepsis or organ dysfunction, provided there are no contraindications to enteral feeding⁽³²⁾.

Malnutrition in children remains a critical public health issue in the 21^st century, significantly impacting growth, development and survival worldwide. Despite global efforts, undernutrition – including stunting, wasting and micronutrient deficiencies – continues to affect millions of children, particularly in low- and middle-income countries. Concurrently, the emergence of childhood overweight and obesity introduces a complex double burden of malnutrition. Early-life nutrition is crucial, as the first 1000 days represent a vital window for interventions to optimize immune function and long-term health outcomes. Sustainable progress requires integrated strategies encompassing improved maternal and child nutrition, food security, healthcare access and education. Prioritizing child nutrition is essential to breaking the cycle of malnutrition and ensuring healthier futures for generations to come.

Autor corespondent: Bogdan-Aurelian Stana E-mail: bogdan.stana@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.