Biochemical changes in SAM

Protein-Energy Malnutrition (PEM), particularly its severe forms (Marasmus, Kwashiorkor, and Marasmic-Kwashiorkor), is characterized by profound biochemical, metabolic, and physiological changes. These changes are driven by the body's attempt to survive despite inadequate intake, a process known as "Reductive Adaptation."

1. General Pathophysiology: Reductive Adaptation

• Definition: The systems of the body "shut down" or slow down to conserve energy and prolong life. This state effectively resembles hibernation,.
• Mechanism:
  • Basal Metabolic Rate (BMR) is reduced.
  • Functional reserve of organs is diminished.
  • Inflammatory and immune responses are downregulated.
• Consequences: While this adaptation allows survival on limited calories, it leaves the child with a "fragile" physiology. Minor stresses (infection, rapid feeding, fluids) can overwhelm these reduced homeostatic capacities and precipitate death.

2. Hormonal Profile and Adaptation

The biochemical landscape of PEM is dictated by a specific hormonal milieu designed to mobilize endogenous stores (catabolism) while limiting tissue synthesis (anabolism).

A. Cortisol (The Catabolic Driver)

• Levels: Plasma cortisol levels are generally high, especially in Marasmus, due to the stress of malnutrition and infection. In Kwashiorkor, free cortisol is high due to a lack of cortisol-binding globulin, though adrenal exhaustion may eventually lower total levels,.
• Metabolic Effects:
  • Carbohydrates: Increases gluconeogenesis from amino acids and decreases peripheral glucose utilization (antagonistic to insulin) to maintain blood glucose.
  • Proteins: Mediates muscle proteolysis to supply the amino acid pool.
  • Lipids: Promotes lipolysis to maintain the fatty acid pool for energy.

B. Insulin (The Anabolic Failure)

• Levels: Insulin levels are low. This reduction is adaptive to prevent hypoglycemia in the face of low intake. In Kwashiorkor, beta-cell dysfunction or exhaustion may lead to very low levels.
• Metabolic Effects:
  • Proteins: Low insulin leads to reduced protein synthesis and muscle wasting.
  • Lipids: The lack of insulin's inhibitory effect on lipolysis allows fat mobilization. However, the failure of insulin-mediated lipogenesis in the liver contributes to the failure to clear hepatic fat (see Fatty Liver).

C. Growth Hormone (GH)

• Levels: GH levels are typically elevated, particularly in Kwashiorkor.
• Stimuli for release: Hypoglycemia, low fatty acid pool, protein depletion (albumin < 3 g/dL), and altered amino acid profile (low branched-chain amino acids),.
• Metabolic Effects:
  • Insulin Antagonism: High GH inhibits glucose uptake by tissues, conserving it for the brain.
  • Lipolysis: Increases fatty acid mobilization.
  • Paradox: Despite high GH, growth is arrested because the production of Somatomedins (IGF-1) is suppressed by malnutrition.

D. Somatomedins (IGF-1)

• Levels: Insulin-like Growth Factor-1 (IGF-1) levels are very low, especially in Kwashiorkor.
• Significance: This uncouples the lipolytic action of GH from its growth-promoting effects.

3. Protein and Nitrogen Metabolism

Protein metabolism is characterized by a dramatic reduction in synthesis and a shift in the production of specific proteins.

A. Serum Proteins

• Albumin:
  • Synthesis is reduced by up to 50% to conserve amino acids.
  • Catabolism is also reduced, and there is a shift from extravascular to intravascular pools to maintain levels initially.
  • In severe PEM (especially Kwashiorkor), levels fall below 2.5–3.0 g/dL. Levels < 2.0 g/dL are associated with high mortality.
• Globulins:
  • Alpha-1 Globulins: Often increased as these include "Acute Phase Reactants" (e.g., alpha-1 antitrypsin). The liver prioritizes their synthesis over albumin during infection/stress,.
  • Beta-Globulins: Reduced. This fraction includes carrier proteins like Transferrin and Beta-lipoprotein. Transferrin levels < 0.45 mg% indicate severe PEM.
  • Gamma-Globulins: Usually increased due to infection, but may be low in terminal stages due to immune exhaustion.

B. Amino Acid Pool

• Total Pool: Plasma amino acid pool may decrease by 50%.
• Ratio Inversion: There is a specific reduction in Essential Amino Acids (EAA), particularly Branched-Chain Amino Acids (BCAA) (Valine, Leucine, Isoleucine).
• Whitehead's Ratio: The ratio of Non-Essential to Essential Amino Acids (NEAA/EAA) increases. In Kwashiorkor, this ratio often exceeds 3.5 (Normal is ~1.5),.
• Specific Deficits:
  • Alanine: Levels are low in Kwashiorkor as it is used as a substrate for gluconeogenesis.
  • Tyrosine/Phenylalanine: Metabolism is often impaired.

C. Enzymes

• Serum enzymes (e.g., amylase, lipase, cholinesterase) are reduced.
• Muscle enzymes fall before serum levels.
• Urea Cycle: Urea production is decreased due to low protein intake, leading to low Blood Urea Nitrogen (BUN).

4. Lipid Metabolism and Fatty Liver

Changes in lipid metabolism distinguish Marasmus from Kwashiorkor.

A. Fatty Liver (Steatosis)

• Occurrence: Characteristic of Kwashiorkor; absent or mild in Marasmus.
• Pathogenesis:
  • Increased Flux: High cortisol and GH levels stimulate lipolysis in adipose tissue, sending a flux of free fatty acids (FFA) to the liver.
  • Impaired Secretion: The liver cannot export these fats because the synthesis of Beta-lipoprotein (VLDL) is impaired due to a lack of amino acids (specifically apoproteins),.
  • Result: Triglycerides accumulate in hepatocytes, starting from the periphery of the lobule,.

B. Serum Lipids

• Serum cholesterol, triglycerides, and phospholipids are generally low.
• Low serum cholesterol and phospholipid levels are biochemical predictors of mortality.

5. Carbohydrate Metabolism

• Hypoglycemia:
  • Defined as blood glucose < 54 mg/dL (< 3 mmol/L) in SAM.
  • Cause: Glycogen stores in the liver and muscle are depleted. Gluconeogenesis is the primary source of glucose but can be overwhelmed by infection or fasting,.
  • Presentation: Often asymptomatic; part of the lethal triad (Hypoglycemia, Hypothermia, Infection).
• Glucose Intolerance: Glucose tolerance curves may be diabetic in type due to tissue insulin resistance and chromium deficiency,.

6. Water and Electrolyte Disturbances

The regulation of body fluids and electrolytes is severely compromised, largely due to the failure of energy-dependent ion pumps.

A. The "Cell Pump" Failure

• The Na+/K+ ATPase pump requires ATP to keep potassium inside cells and sodium outside. In SAM, energy deficiency causes this pump to slow down.
• Result: Potassium leaks out of cells, and Sodium leaks in.

B. Total Body Electrolytes

• Potassium (K+): Total body potassium is severely depleted due to muscle breakdown and leakage from cells, even if serum potassium appears normal,.
• Sodium (Na+): Total body sodium is increased (intracellular accumulation), even though serum sodium may be low (dilutional hyponatremia). This makes children intolerant to salt loads,.
• Magnesium (Mg++): Total body magnesium is depleted.
• Calcium & Phosphorus: Generally low; hypophosphatemia is a major risk during refeeding,.

C. Pathogenesis of Oedema in Kwashiorkor

Oedema is multifactorial and not solely due to low albumin,.

1. Hypoalbuminemia: Reduces oncotic pressure, but is not the only cause.
2. Hormonal Retention: Reduced cardiac output and renal blood flow trigger the Renin-Angiotensin-Aldosterone system, causing fluid retention.
3. Hepatic Impairment: Reduced inactivation of Antidiuretic Hormone (ADH) and Aldosterone by the fatty liver.
4. Ferritin: Increased ferritin may act as an ADH-like substance.
5. Free Radicals: Oxidative damage to capillary permeability (Golden's Theory).

7. Micronutrients and Trace Elements

• Iron:
  • Red blood cell mass is reduced, releasing iron.
  • This iron is stored as ferritin (unavailable for erythropoiesis).
  • Free Iron: "Extra" free iron is present and promotes bacterial growth and free radical formation. Therefore, iron supplementation is contraindicated in the initial stabilization phase.
• Zinc:
  • Levels are markedly depressed.
  • Deficiency contributes to skin changes, anorexia, and immune dysfunction.
• Copper:
  • Levels are low. Deficiency causes neutropenia and bone changes.
• Vitamins:
  • Vitamin A: Hepatic stores are depleted; risk of blindness is high.
  • Vitamin D: Rickets may be masked by growth arrest but manifests during recovery.

8. Immunological Biochemistry

• Nutritionally Acquired Immunodeficiency:
  • Cell-Mediated Immunity: Atrophy of the thymus and lymphoid tissue leads to reduced T-cells and impaired delayed hypersensitivity (e.g., negative Mantoux even with TB).
  • Humoral Immunity: B-cell function is relatively preserved; Immunoglobulin levels are often normal or elevated (due to repeated infections), but specific antibody response to new antigens is poor,.
  • Phagocytosis: Impaired; reduced glycolytic energy for engulfment and bacterial killing.
  • Complement: Components are reduced.

9. Oxidative Stress

• Imbalance: There is an excess production of free radicals (due to infection and free iron) and a severe deficiency of antioxidants (Vitamin A, C, E, Zinc, Selenium, Glutathione),.
• Damage: This oxidative stress damages cell membranes, contributing to the skin lesions ("flaky paint dermatosis") and oedema of Kwashiorkor,.

10. Organ-Specific Biochemical Changes

• Brain: Reduced lipids (cholesterol, phospholipids), DNA, RNA, and neurotransmitters. This leads to functional isolation and developmental delay,.
• Kidney: Reduced Glomerular Filtration Rate (GFR) and inability to excrete acid load or excess sodium.
• Gastrointestinal Tract: Mucosal atrophy leads to disaccharidase deficiency (specifically lactase), causing osmotic diarrhea and malabsorption,.

Summary Table of Key Biochemical Findings