Level 01 · The Upstream Trigger
Chronic HPA Axis Activation — Sustained Cortisol Elevation
The hypothalamic-pituitary-adrenal axis responds to any perceived threat — physical, psychological, inflammatory, or glycaemic — with a cortisol release. In acute stress this is protective. In chronic, sustained activation the cortisol signal becomes the problem: it directly suppresses the parasympathetic nervous system, which is the division of the autonomic nervous system that runs digestion. You cannot be in fight-or-flight and digest food simultaneously. The body is not designed for both.
Cortisol suppresses vagal tone
Level 02 · Primary Digestive Impairment
Reduced Stomach Acid (Hypochlorhydria) and Impaired Enzyme Output
The vagus nerve carries the parasympathetic signal that initiates the cephalic phase of digestion — the pre-meal preparation that starts acid and enzyme secretion before food even arrives. When vagal tone is chronically low, this preparation is incomplete. Stomach acid (HCl) falls. Intrinsic factor production falls with it. Pancreatic enzyme output is reduced. Bile flow is impaired. The entire digestive machinery is running at reduced capacity — not because of any pathology in the gut itself, but because of a signal failure originating in the nervous system.
Low HCl impairs protein unfolding and mineral release
Level 03 · Secondary Malabsorption
Impaired Protein Digestion and Reduced Mineral and Vitamin Absorption
Stomach acid performs three critical functions: it denatures dietary protein so pepsin can begin peptide cleavage; it releases mineral ions (zinc, iron, magnesium, calcium) from their food matrix so they can be absorbed in the small intestine; and it creates the acidic environment that activates intrinsic factor binding to vitamin B12. Without adequate HCl, all three processes are compromised simultaneously. Protein arrives in the small intestine inadequately digested. Minerals remain bound in their food matrix, unavailable for absorption. B12 travels through without binding to intrinsic factor, passing out in stool regardless of dietary intake.
Depleted micronutrients produce systemic consequences
Level 04 · Downstream Deficiencies
Zinc, B12, and Iron — Three Deficiencies With Overlapping Systemic Effects
These three micronutrients, all dependent on adequate stomach acid for absorption, have the widest systemic reach of any nutrients in the body:
Zinc — required for over 300 enzyme reactions, T-cell maturation, thymic hormone production, wound healing, testosterone synthesis, taste and smell, and insulin signalling. Low zinc produces immune suppression, poor skin integrity, impaired recovery, and hormonal disruption.
Vitamin B12 — required for myelin sheath synthesis, red blood cell production, homocysteine methylation, SAMe production, and nervous system function. Low B12 produces neuropathy, fatigue, elevated homocysteine, methylation impairment, cognitive symptoms, and macrocytic anaemia.
Iron — required for haemoglobin oxygen transport, mitochondrial electron transport, thyroid peroxidase activity, and neurotransmitter synthesis. Low iron (ferritin) produces fatigue, cold intolerance, hair loss, brain fog, restless legs, and impaired thyroid conversion.
Zinc — required for over 300 enzyme reactions, T-cell maturation, thymic hormone production, wound healing, testosterone synthesis, taste and smell, and insulin signalling. Low zinc produces immune suppression, poor skin integrity, impaired recovery, and hormonal disruption.
Vitamin B12 — required for myelin sheath synthesis, red blood cell production, homocysteine methylation, SAMe production, and nervous system function. Low B12 produces neuropathy, fatigue, elevated homocysteine, methylation impairment, cognitive symptoms, and macrocytic anaemia.
Iron — required for haemoglobin oxygen transport, mitochondrial electron transport, thyroid peroxidase activity, and neurotransmitter synthesis. Low iron (ferritin) produces fatigue, cold intolerance, hair loss, brain fog, restless legs, and impaired thyroid conversion.
Systemic consequences across multiple organ systems
Level 05 · Clinical Presentations
What the Client Presents With — Seemingly Unrelated Symptoms From One Upstream Driver
Neurological
Brain fog, numbness and tingling, poor memory, anxiety, depression, peripheral neuropathy — all B12 and iron dependent
Immune
Frequent infections, slow wound healing, autoimmune flares, poor vaccine response — all zinc and B12 dependent
Bone and Structural
Poor bone density, stress fractures, joint pain — zinc required for osteoblast activity; calcium absorption impaired by low HCl
Energy and Metabolism
Profound fatigue, cold intolerance, poor exercise recovery — iron and B12 both required for mitochondrial ATP production
Gut Symptoms
Bloating, belching, reflux (paradoxically from low not high acid), constipation, undigested food in stool
Hormonal and Recovery
Low testosterone (zinc), poor muscle synthesis (protein maldigestion), low progesterone (B6 and zinc), poor thyroid conversion (iron)
The clinical point
A client presenting with brain fog, fatigue, frequent infections, poor gut function, and low mood is not presenting with five separate problems. They are presenting with the downstream consequences of one upstream driver — chronic HPA axis activation suppressing the parasympathetic nervous system that runs their digestion. The GP treats each symptom in isolation. The functional medicine approach tests the upstream driver and the downstream deficiencies, then addresses them in sequence.
What testing identifies at each level
DUTCH Plus
Cortisol diurnal pattern · CAR · HPA stage · Cortisol metabolites
Blood Chemistry
Ferritin · B12 · Zinc · Homocysteine · MCV · RBC · Iron saturation
GI-MAP
Elastase (pancreatic output) · Fat and protein digestion markers · Dysbiosis driven by low HCl
OAT
Methylmalonic acid (B12 functional status) · Citrate/isocitrate (mitochondrial iron) · B6 markers
Test the upstream driver — not just the downstream symptoms
The TDG Five-Test Programme identifies where the cascade starts for you specifically — cortisol pattern, digestive capacity, nutrient status, and mitochondrial function in one clinical picture.