Malnutrition — Protein-Energy

• Depletion of Macronutrient Stores and Substrate Mobilization: In the immediate postabsorptive state (6-12 hours of inadequate intake), hepatic glycogen becomes depleted, triggering activation of counter-regulatory hormones (glucagon, catecholamines, cortisol) and sympathetic nervous system activation. These hormonal changes promote lipolysis in adipose tissue via hormone-sensitive lipase activation, increasing circulating free fatty acids. Simultaneously, muscle proteolysis is activated through the ubiquitin-proteasome system and autophagy pathways, driven by increased cortisol and reduced insulin signaling. The amino acids released from muscle (particularly alanine and glutamine) are converted to glucose via hepatic gluconeogenesis to maintain blood glucose for obligate glucose-dependent tissues (brain, red blood cells). As PEM progresses over days to weeks, the body preferentially oxidizes fat stores while attempting to spare protein, but eventually protein catabolism becomes the dominant source of gluconeogenic substrate. This adaptive mechanism becomes maladaptive as essential proteins comprising structural and functional components are degraded, leading to progressive organ dysfunction.

• Insulin Resistance and Altered Hormone Signaling: Early PEM is characterized paradoxically by hyperinsulinemia relative to the degree of nutrient availability, which may represent an adaptive response to preserve existing lean mass. However, as severe malnutrition develops, insulin levels decline substantially while insulin resistance at the cellular level increases due to reduced insulin receptor density and impaired intracellular signaling (decreased GLUT4 translocation). This combination creates a metabolic milieu favoring catabolism. Concurrently, thyroid hormone metabolism shifts toward increased reverse T3 (rT3) production and decreased T3 levels, reducing metabolic rate as an energy-conservation mechanism. Growth hormone secretion increases but tissue responsiveness to IGF-1 (insulin-like growth factor-1) is markedly diminished due to inadequate hepatic production and reduced peripheral conversion of IGF-1 from IGFBP complexes. This hormonal milieu actively suppresses anabolism and perpetuates catabolism.

• Micronutrient Depletion and Enzyme Cofactor Deficiency: Beyond macronutrient depletion, PEM invariably involves deficiencies of essential micronutrients (thiamine, niacin, riboflavin, ascorbic acid, vitamin A, vitamin D, selenium, zinc, iron, and magnesium) that serve as critical cofactors for hundreds of enzymatic reactions. Thiamine (vitamin B1) deficiency impairs pyruvate dehydrogenase and transketolase activity, disrupting both aerobic metabolism and the pentose phosphate pathway essential for NADPH generation and nucleotide synthesis. Zinc deficiency compromises immune function by reducing thymulin activity and T-cell development, impairing wound healing through decreased collagen synthesis (requiring zinc-dependent prolyl and lysyl hydroxylases), and reducing protein synthesis capacity. Selenium deficiency diminishes glutathione peroxidase activity, increasing oxidative stress. Vitamin C deficiency impairs collagen cross-linking and immune function through effects on neutrophil chemotaxis and T-cell proliferation. These micronutrient deficiencies explain many clinical manifestations of PEM beyond simple energy deficit, including immune dysfunction, poor wound healing, and impaired recovery.

• Lean Tissue Wasting and Organ Dysfunction: Progressive protein catabolism affects all organs, but critical functional tissues including respiratory muscles, cardiac myocytes, intestinal epithelium, and immune organs are particularly vulnerable. Respiratory muscle weakness from decreased diaphragmatic mass and strength predisposes to aspiration pneumonia and respiratory failure; this is a major mechanism of mortality in severe PEM. Cardiac atrophy with reduced contractile protein content leads to decreased cardiac output, hypotension, and bradycardia (documented in both marasmus and kwashiorkor). The intestinal epithelial barrier undergoes atrophy with flattening of villi and reduced tight junction protein expression (claudins, occludin, zonula occludens-1), resulting in increased intestinal permeability, bacterial translocation, and systemic endotoxemia—a key mechanism linking malnutrition to infection. Immune organ atrophy (thymic involution, splenic atrophy) combined with reduced lymphocyte proliferation, impaired antibody synthesis, and altered complement activation creates profound immunosuppression. The gastrointestinal mucosa shows reduced gastric acid secretion and impaired pancreatic enzyme secretion, perpetuating malabsorption even when nutrition is reintroduced.

• Metabolic Acidosis and Electrolyte Derangements: Chronic PEM produces metabolic acidosis through both starvation ketosis (from accelerated lipolysis producing ketone bodies exceeding clearance) and uremia (from reduced glomerular filtration secondary to decreased muscle mass and renal hypoperfusion). Phosphate depletion occurs despite its relative abundance in food because urinary conservation mechanisms become impaired, and reintroduction of nutrition can precipitate refeeding syndrome with severe hypophosphatemia, hypokalemia, and hypomagnesemia as the sudden shift from catabolism to anabolism increases ATP demand and drives these electrolytes intracellularly. Sodium and water retention becomes paradoxically pronounced in kwashiorkor-type PEM due to reduced plasma albumin (oncotic pressure reduction), increased ADH and renin-angiotensin system activity, and impaired hepatic inactivation of hormones.

• Inadequate Dietary Intake (Primary PEM): Most common globally, occurring in poverty, food insecurity, starvation, restricted access to food during conflict or natural disasters, and eating disorders (anorexia nervosa). In hospitalized patients, inadequate intake may result from decreased appetite, dysphagia, NPO status, or iatrogenic factors (delayed feeding advancement, inadequate caloric provision in standard hospital diets). Infants and young children are particularly vulnerable due to high caloric requirements relative to body weight and dependence on caregivers.

• Malabsorption and Chronic Gastrointestinal Disease: Celiac disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), tropical sprue, Whipple's disease (Tropheryma whipplei), cystic fibrosis, chronic pancreatitis with pancreatic insufficiency, short bowel syndrome from extensive resection, hepatic cirrhosis with portal hypertension and varices reducing oral intake, and cholestasis all predispose to malabsorption of macronutrients and micronutrients. Post-gastrectomy or post-bariatric surgery patients may develop PEM years after intervention due to reduced absorptive surface area and altered nutrient transit.

• Increased Metabolic Demands: Severe infection/sepsis, trauma, major surgery, burn injury (with losses proportional to burn size—burn victims may require 1.5-2× normal caloric requirements), malignancy (especially with active cachexia from tumor necrosis factor-alpha and interleukin-6 production), chronic kidney disease and end-stage renal disease (ESRD), cardiac cachexia in advanced heart failure, and hyperthyroidism (including Graves' disease and thyroiditis). Tuberculosis, HIV/AIDS (particularly with high viral loads or opportunistic infections), and chronic inflammatory conditions all increase metabolic rate substantially.

• Medication and Treatment-Related Factors: Medications causing anorexia (chemotherapy agents, some antibiotics), diarrhea (broad-spectrum antibiotics disrupting microbiota, magnesium supplements), or nutrient malabsorption (certain anticonvulsants affecting vitamin D and folate metabolism), as well as side effects from radiotherapy to the head/neck or abdomen impairing taste, swallowing, or nutrient absorption.

• Behavioral and Socioeconomic Factors: Substance use disorders, alcoholism (both from reduced intake and hepatic disease), psychiatric illness, social isolation in elderly patients, poverty, food insecurity, and lack of access to healthcare. Elderly patients are at particular risk due to combination of multiple comorbidities, polypharmacy, age-related changes in taste and smell, dental disease, difficulty swallowing, and reduced appetite-regulating hormone sensitivity.

• Marasmus (Chronic PEM with Balanced Deficiency): Results from prolonged, relatively equal deficiency of all macronutrients and calories. Patients present with severe wasting affecting both muscle and fat compartments—the body appears emaciated with prominent bony landmarks (ribs, vertebrae, pelvis clearly visible), minimal subcutaneous fat, and marked muscle atrophy visible in temporal regions, interosseous spaces, and lower extremities. Body weight is typically <60% of ideal body weight. Characteristic appearance includes a "wizened" or aged facial expression, prominent ribs and vertebral column, and skin hanging loosely. Patients are usually alert and maintain relatively preserved appetite. Complications include reduced infection rates initially (due to impaired inflammatory response) but eventual severe immunosuppression, hypothermia (reduced metabolic rate), and multiple organ dysfunction. Laboratory findings show proportional reduction in serum albumin and prealbumin, normal or only mildly elevated inflammatory markers initially.

• Kwashiorkor (Acute-on-Chronic PEM with Protein Preference): Results from relative protein deficiency in the setting of adequate to moderate carbohydrate and caloric intake (historically described in infants transitioned from breast milk to starch-based diets). Distinctive features include dependent edema (pitting edema of lower extremities, sometimes face and hands) paradoxically occurring despite malnutrition and weight loss—edema results from severe hypoalbuminemia (<2.0 g/dL) causing reduced plasma oncotic pressure combined with sodium and water retention from hormonal changes and impaired hepatic function. Other characteristic findings include hepatomegaly (from fatty infiltration despite apparent catabolic state), skin changes including hyperkeratosis with desquamation, hyperpigmented patches, and peeling "flaky paint" dermatitis (particularly on pressure points and areas of irritation), hair changes (hair becomes fine, straight, and depigmented with "flag sign"—transverse bands of depigmentation reflecting periods of protein deficiency), and moon facies from facial edema. The mental status is often altered, ranging from lethargy to irritability. Laboratory findings show markedly reduced serum albumin and prealbumin, elevated acute-phase reactants (reflecting inflammatory response often triggered by acute infection or stress precipitating the acute decompensation), anemia, and evidence of hepatic dysfunction (elevated transaminases, prolonged PT/INR, hypoglycemia). Mortality is substantially higher than in marasmus due to greater metabolic derangements.

• Intermediate Presentations (Marasmic-Kwashiorkor): Patients with evidence of both severe wasting and edema, representing combinations of chronic and acute nutritional stress.

• General Systemic Symptoms: Across all presentations, patients commonly report fatigue and weakness proportional to muscle loss, poor appetite, cold intolerance, amenorrhea or reduced libido (from malnutrition-induced suppression of GnRH and gonadal hormones), and cognitive difficulties ranging from poor concentration to frank confusion in severe cases.

• Physical Examination Findings:
• Vital signs abnormalities: Hypothermia (core temperature <36°C in severe malnutrition from reduced metabolic rate), bradycardia (resting heart rate often <50 bpm from cardiac atrophy and reduced sympathetic tone), hypotension with orthostatic changes (from reduced intravascular volume, cardiac output, and sympathetic responsiveness), tachypnea paradoxically may appear when respiratory muscles weaken significantly
• Skin and hair: Thin, dry skin with reduced turgor (skin tenting persists >2 seconds when pinched), hair easily pluckable, alopecia in severe cases, poor wound healing, dermatitis in areas of friction
• Musculoskeletal: Visible ribs, prominent bony prominences, atrophy of temporal muscles (creating "skull-like" appearance), reduced muscle bulk in extremities, loss of normal muscle definition, sometimes contrasting with preserved subcutaneous fat in kwashiorkor
• Edema: Dependent pitting edema in kwashiorkor and mixed presentations, sometimes involving periorbital tissues
• Hepatomegaly: Often present in kwashiorkor despite weight loss, reflecting hepatic steatosis and impaired protein synthesis
• Neurological findings: Diminished reflexes (particularly ankle reflexes), reduced peripheral sensation in advanced cases, tetany or tremors from electrolyte abnormalities (hypocalcemia, hypomagnesemia), confusion or altered mental status in severe cases

• Anthropometric Assessment: Body Mass Index (BMI) calculated as weight(kg)/height(m)² provides population-level classification—BMI <18.5 kg/m² defines underweight status in adults, with BMI <16 kg/m² indicating significant undernutrition. However, BMI is limited in acute settings where rapid weight loss may not yet reflect lean tissue loss. Percent ideal body weight (%IBW) is useful for comparison—%IBW <80% indicates mild-moderate malnutrition, <70% indicates moderate malnutrition, and <60% indicates severe malnutrition. Unintentional weight loss exceeding 10% of usual body weight over 6 months or >5% over 1 month is pathologically significant. Mid-arm muscle circumference (MAMC) measured at the midpoint of the non-dominant upper arm reflects muscle mass; MAMC <16.5 cm in men or <14.5 cm in women suggests significant muscle depletion. Triceps skinfold thickness (TSF) measured with calipers reflects subcutaneous fat stores; marked reduction indicates fat compartment depletion (though this is operator-dependent and less reliable).

• Serum Protein and Visceral Protein Markers:
• Serum albumin (normal 3.5-5.0 g/dL) is the most commonly measured but has reduced sensitivity and specificity for acute malnutrition because of its long half-life (20 days), multiple non-nutritional factors affecting synthesis (hepatic disease, inflammation, proteinuria), and delayed changes in early malnutrition. However, albumin <3.0 g/dL is consistently associated with poor outcomes and increased infection risk. In kwashiorkor, albumin is characteristically very low (<2.0 g/dL).
• Prealbumin (transthyretin) (normal 20-40 mg/dL) has a shorter half-life (2-3 days) and is therefore more sensitive for detecting acute nutritional changes and monitoring response to refeeding. Prealbumin <20 mg/dL indicates protein malnutrition; levels <11 mg/dL correlate with severe malnutrition and increased mortality. However, prealbumin is an acute-phase reactant and may be elevated in inflammation even with malnutrition, limiting specificity.
• Total serum protein and serum transferrin are less specific but provide additional context.

• Nitrogen Balance and Metabolic Studies: In hospitalized patients, 24-hour urinary urea nitrogen measurement combined with dietary protein intake allows calculation of nitrogen balance (nitrogen intake minus nitrogen losses in urine and feces; positive balance indicates net protein synthesis, negative indicates net catabolism). **Creatinine-height

Immediate stabilisation (WHO "10 steps" for severe acute malnutrition)

• Hypoglycemia: treat first — oral or NG glucose/sucrose if alert, IV dextrose if obtunded, then frequent feeds. Depleted glycogen plus impaired gluconeogenesis makes hypoglycemia a leading early cause of death.
• Hypothermia: passive rewarming/skin-to-skin; hypothermia and hypoglycemia usually coexist and both signal occult sepsis.
• Dehydration: WHO advises oral/NG low-sodium, high-potassium rehydration solution (ReSoMal) rather than standard ORS, because total body sodium is high and potassium low. IV fluids are reserved for shock — the atrophic myocardium tolerates volume poorly.
• Infection: WHO recommends empiric antibiotics for all children with complicated severe acute malnutrition (parenteral ampicillin plus an aminoglycoside such as gentamicin; oral amoxicillin for uncomplicated cases managed at home), since fever and leukocytosis are frequently absent.

Nutritional therapy

• Stabilisation feeding: low-protein, low-lactose, low-osmolar F-75 formula (75 kcal/100 mL) in small frequent feeds — deliberately not calorie-loaded, to avoid refeeding syndrome and cardiac failure.
• Catch-up growth: transition to F-100 or ready-to-use therapeutic food (RUTF) once edema resolves and appetite returns.
• Micronutrients: thiamine before any carbohydrate load, plus zinc, potassium, magnesium, folate and vitamin A. Iron is withheld during stabilisation (free iron fuels oxidative injury and bacterial growth) and started only in the rehabilitation phase.
• Route: enteral first — ASPEN/SCCM guidance favors enteral over parenteral nutrition whenever the gut works; use NG feeding for poor intake and PEG for durable dysphagia. Parenteral nutrition only for a nonfunctional gut.

Contraindicated / avoid

• Diuretics for kwashiorkor edema — the edema is oncotic and hormonal, not volume overload; diuresis worsens hypovolemia and hypokalemia.
• Rapid high-calorie or high-protein refeeding, IV albumin, and unmonitored IV fluids.
• ASPEN's 2020 refeeding consensus advises starting at a markedly reduced calorie target, advancing over days, with electrolyte repletion before and during advancement.

Emergencies of the disease itself

• Hypoglycemia: glycogen depletion plus failing gluconeogenesis; signaled by lethargy, hypothermia, seizure, or unexplained obtundation. Check a glucose in any malnourished patient with altered mental status.
• Sepsis and bacterial translocation: villous atrophy and loss of tight-junction integrity allow enteric organisms into portal blood, while thymic involution and impaired opsonization blunt clearance. The signal is absence of fever and leukocytosis — hypothermia, hypoglycemia, or new lethargy may be the only clue.
• Respiratory failure: diaphragmatic and intercostal wasting reduce vital capacity and cough; signaled by rising respiratory rate then hypercapnia, and by failure to wean from ventilation.
• Cardiac failure: atrophied myocardium with low stroke volume decompensates when given IV fluids, blood, or sodium loads; signaled by tachycardia, rising JVP, hepatomegaly, and basal crackles.

Complications of treatment

• Refeeding syndrome: carbohydrate-driven insulin surge shifts phosphate, potassium and magnesium intracellularly for ATP and 2,3-BPG synthesis. Hypophosphatemia is the hallmark and produces rhabdomyolysis, hemolysis, ventricular arrhythmia, respiratory muscle failure, and delirium. Hypokalemia and hypomagnesemia add QT prolongation and torsades — an emergency. ASPEN's 2020 consensus advises pre-emptive electrolyte and thiamine repletion with slow calorie advancement.
• Wernicke encephalopathy: thiamine stores are exhausted and glucose loading consumes remaining cofactor; confusion, ophthalmoplegia, ataxia after refeeding. Give thiamine before dextrose.
• Fluid overload from over-rehydration and osmotic diarrhea from hyperosmolar or lactose-containing feeds.
• Catheter-related bloodstream infection and hepatic steatosis/cholestasis with parenteral nutrition; aspiration pneumonia with enteral feeding.

Chronic sequelae

• Growth stunting and irreversible cognitive/neurodevelopmental deficits when malnutrition occurs in the first 1000 days.
• Impaired wound healing, pressure ulcers, surgical dehiscence from deficient collagen synthesis (zinc- and vitamin C–dependent hydroxylases).
• Vitamin A deficiency with xerophthalmia and keratomalacia, a preventable cause of childhood blindness.

• Marasmus vs kwashiorkor in one line: marasmus = total calorie deficit, emaciated "wizened old man" facies, no edema, preserved appetite; kwashiorkor = relative protein deficit with adequate carbohydrate, edema plus hepatomegaly, flaky-paint dermatitis, and the flag sign of banded hair depigmentation. Edema is the discriminator.
• Fatty liver in kwashiorkor is the mechanism examiners love: inadequate apolipoprotein B synthesis blocks VLDL export, so triglyceride accumulates hepatically — hepatomegaly in a starving child is not a distractor, it is the diagnosis.
• Single best next step in a lethargic severely malnourished child: check and treat glucose, then warm the patient, then give empiric antibiotics — hypoglycemia, hypothermia and occult sepsis are the triad that kills in the first 48 hours (WHO stabilisation sequence).
• Refeeding syndrome hinges on hypophosphatemia. A patient who becomes weak, arrhythmic, or confused a few days after feeding restart has a low phosphate until proven otherwise; give thiamine before glucose (ASPEN 2020).
• Do not give iron during stabilisation and do not give diuretics for kwashiorkor edema — both are the classic wrong answers. Use ReSoMal (low sodium, high potassium), not standard ORS, and avoid IV fluids unless the child is in shock.
• Albumin is a poor nutrition marker — it is a negative acute-phase reactant with a long half-life; prealbumin responds faster but is also inflammation-sensitive. A low albumin in an inflamed patient reflects illness severity, not simply protein intake.
• The association tested: severe acute malnutrition confers measles, diarrheal disease, and tuberculosis susceptibility out of proportion to any single deficiency, via thymic atrophy and mucosal barrier failure — and infection may present without fever.
• Common distractor: a normal or obese BMI does not exclude protein-energy malnutrition; ASPEN/Academy of Nutrition and Dietetics criteria weight unintentional weight loss, reduced intake, and loss of muscle mass and subcutaneous fat over BMI alone.