What symptoms can low adrenocorticotropic hormone (ACTH) cause?

Symptoms of Low ACTH (Secondary Adrenal Insufficiency)

Low ACTH causes secondary adrenal insufficiency, presenting with fatigue, weakness, nausea, weight loss, hypoglycemia, and hyponatremia—but notably without the hyperpigmentation or hyperkalemia seen in primary adrenal insufficiency. 1

Core Clinical Manifestations

Constitutional Symptoms

• Fatigue and weakness are the most common presenting symptoms, often progressive and debilitating enough to interfere with daily activities and work performance 2, 3, 4
• Anorexia and unintentional weight loss occur frequently, with patients reporting poor appetite particularly in the morning 1, 4
• Nausea and vomiting are present in 20-62% of cases, often accompanied by abdominal pain that can mimic acute surgical conditions 1, 3
• Morning nausea and lack of appetite are particularly characteristic, representing under-replacement or undiagnosed disease 1

Metabolic and Electrolyte Disturbances

• Hypoglycemia is a hallmark feature, especially in children and during fasting states, and may present with seizures 3, 5, 4
• Hyponatremia occurs in 90% of newly diagnosed cases, though it may be mild or even absent in secondary AI since mineralocorticoid function remains intact 1, 6
• Hyperkalemia is typically absent in secondary AI because aldosterone secretion continues normally via the renin-angiotensin system 7, 1

Cardiovascular Manifestations

• Hypotension can occur but is generally less severe than in primary AI, since mineralocorticoid deficiency is absent 7, 4
• Orthostatic symptoms may be present but are milder compared to primary adrenal insufficiency 1

Neuropsychiatric Features

• Altered mental status, confusion, and difficulty concentrating are common, with some patients requiring psychotherapy or antidepressant treatment that resolves once glucocorticoid replacement begins 3, 4
• Deteriorating school or work performance may be an early subtle sign in children and adults 3
• Irritability and mood changes frequently accompany the physical symptoms 3

Distinguishing Features from Primary AI

• Normal skin coloration without hyperpigmentation is the key distinguishing feature, because ACTH levels are low rather than elevated 1, 4
• Absence of salt craving, since mineralocorticoid function is preserved 1
• No hyperkalemia, present in only ~50% of primary AI but essentially absent in secondary AI 1

Critical Presentations Requiring Emergency Recognition

Acute Adrenal Crisis

• Severe weakness, confusion, and altered consciousness progressing to coma can occur during acute decompensation 1, 2
• Unexplained collapse with hypotension and gastrointestinal symptoms (severe vomiting or diarrhea) should immediately trigger suspicion 1
• Hypothermia (as low as 29°C) has been reported in neonatal cases 3
• "Apparent death" at birth or severe neonatal hypoglycemia with seizures characterizes congenital forms 3, 5

Laboratory Clues

• Mild anemia, lymphocytosis, and eosinophilia may be present on routine blood work 4, 2
• Mild hypercalcemia occurs in 10-20% of cases 1
• Increased creatinine from prerenal azotemia reflects volume depletion 1

Common Pitfalls in Diagnosis

• Do not rely on electrolyte abnormalities to make or exclude the diagnosis—hyponatremia may be only marginally reduced and hyperkalemia is absent in secondary AI 1
• Symptoms are often non-specific and patients may be misdiagnosed with depression, chronic fatigue syndrome, or functional disorders before the correct diagnosis is made 3, 4
• Delayed diagnosis is common, with patients in one series presenting to emergency departments 1-3 times over months to years before diagnosis, with symptoms beginning at 3-12 years of age but diagnosis not made until 3.3-14.4 years 3
• Treatment should never be delayed for diagnostic testing if acute adrenal crisis is suspected—administer 100 mg IV hydrocortisone immediately 1

Special Populations

Immune Checkpoint Inhibitor Therapy

• Isolated ACTH deficiency is an increasingly recognized immune-related adverse event from nivolumab, ipilimumab, and other checkpoint inhibitors 2, 6
• Late-onset presentation can occur 4-6 months after discontinuation of the drug, requiring prolonged monitoring 6
• Eosinophilia and subtle electrolyte changes may precede overt symptoms by weeks 2

Neonatal and Childhood Onset

• Prolonged neonatal jaundice, recurrent hypoglycemia, and seizures are the classic triad in congenital isolated ACTH deficiency from TBX19 mutations 5
• Critical illness in the neonatal period with hypothermia and "apparent death" should prompt immediate evaluation 3, 5