Loss of Energy and Constant Fatigue: From Hormones to Genetics

The feeling of fatigue and lack of energy is familiar to everyone. However, when this condition becomes constant, interferes with daily life, and does not go away after rest, it may signal more serious health problems. Constant weakness and loss of energy are not just discomfort, but a symptom that requires attention and thorough diagnostics. The causes can be diverse: from metabolic disorders to serious neurological and cardiovascular diseases.

When Fatigue is Not Just Fatigue: Metabolic and Endocrine Disorders

Our body is a complex system where hormones and metabolism play a key role in maintaining energy. Disruptions in these processes often manifest as chronic fatigue and weakness:

• Protein-Energy Wasting (PEW): This is a condition where the body experiences a deficiency of proteins and energy. It is often observed in children with chronic diseases, manifesting as growth retardation and loss of muscle mass with relative preservation of adipose tissue. PEW is the result of the interaction between chronic inflammation and inadequate nutrition [1].
• Thyroid Diseases: The thyroid gland regulates metabolism, and any of its dysfunctions strongly affect energy levels. Both hyperthyroidism (excess hormones) and hypothyroidism (deficiency) can cause pronounced weakness. In hyperthyroidism, patients may experience psychomotor agitation, disorientation, tachycardia, and weight loss despite a constant feeling of fatigue. Hypothyroidism, conversely, manifests as sluggishness, changes in memory and behavior, hallucinations, and general apathy [5].
• Central Diabetes Insipidus (CDI): This is a rare disease caused by impaired production or secretion of vasopressin (AVP) — a hormone that regulates water balance. AVP deficiency leads to the inability of the kidneys to concentrate urine, causing excessive water loss, severe thirst, and frequent urination (polyuria). These symptoms can be accompanied by pronounced weakness and fatigue. CDI can be caused by tumors, trauma, or autoimmune destruction of the hypothalamus/posterior pituitary neurons [4].

Neurological Causes: From Genetics to Trauma

The nervous system controls all body functions, including movement and perception. Its disorders can directly lead to a feeling of weakness and loss of control over the body:

• Spasticity: This is a motor disorder characterized by increased muscle tone and involuntary contractions. Spasticity is often accompanied by paralysis and can significantly limit activity, causing a feeling of weakness and fatigue due to constant tension. The most common causes of spasticity include stroke, traumatic brain injury, multiple sclerosis, spinal cord injury, and cerebral palsy [3].
• Genetic Factors: In some cases, the cause of weakness lies in genetics. For example, variants of the ATP1A2 gene, which encodes the α2-subunit of Na+/K+-ATPase, are associated with various neurological phenotypes, including familial hemiplegic migraine type 2 (FHM2), epilepsy, and intellectual disability. Such genetic changes can lead to episodes of decreased consciousness, cerebral edema, and, as a consequence, pronounced weakness and functional impairments. Early genetic testing can help determine the cause and prescribe targeted treatment [2].

Cardiovascular System and Aging: Hidden Threats

Heart and vascular health directly affect the delivery of oxygen and nutrients to tissues, and therefore energy levels. Risks increase with age:

• Atrial Fibrillation (AF) and Systemic Inflammation: AF is a common heart rhythm disorder that, especially in combination with systemic inflammation, can negatively affect muscle mass and strength in older adults. Studies show that patients with AF experience a more pronounced decline in functional capabilities, such as an increase in the time required to perform the "chair stand" test. High levels of inflammatory markers, such as interleukin-6 (IL-6) and growth differentiation factor-15 (GDF-15), are also associated with muscle deterioration [6].
• Heart Failure (HF): Elderly patients with HF often develop conditions such as sarcopenia (loss of muscle mass), cachexia (wasting), and general frailty (geriatric asthenia). These conditions significantly exacerbate weakness, reduce quality of life, and pose serious challenges in the treatment of HF in the elderly [8].

Chronic Inflammation and Body Wasting

Chronic inflammation is a common denominator for many conditions causing weakness and energy loss. It can be both a cause and a consequence of various diseases, creating a vicious cycle that depletes the body:

• Relationship with PEW: As already mentioned, protein-energy wasting (PEW) occurs as a result of the interaction between chronic inflammation and inadequate nutrition. Inflammatory processes increase the body's need for energy and proteins while impairing their absorption and metabolism, leading to progressive muscle mass loss and general weakness [1].
• Systemic Inflammation in Chronic Diseases: Many chronic diseases, including cardiovascular (e.g., atrial fibrillation), autoimmune (e.g., multiple sclerosis, autoimmune thyroiditis, certain forms of CDI), and oncological diseases, are accompanied by systemic inflammation. This inflammation can lead to constant fatigue, decreased muscle strength, and general weakness, even if the underlying disease is under control [4, 6].

Given the variety of causes causing weakness and energy loss, it is extremely important not to engage in self-diagnosis and self-medication. Only a qualified doctor can determine the true cause of your condition. Diagnostics may include:

Importance of Diagnostics and Timely Treatment

• Laboratory Tests: General and biochemical blood tests, hormonal studies (e.g., thyroid hormone levels [5]), specific inflammatory markers (IL-6, GDF-15 [6]). Modern methods such as copeptin testing are used to diagnose central diabetes insipidus, which increases the accuracy and acceptability of the diagnostic approach [4].
• Instrumental Studies: Brain MRI (if neurological causes or tumors are suspected [2, 3, 4]), ECG and heart ultrasound (for cardiovascular problems [6, 8]).
• Genetic Testing: In cases where hereditary diseases are suspected, for example, with symptoms associated with ATP1A2 gene variants, early genetic testing is critical to determine the cause and select targeted therapy [2].

Timely and accurate diagnostics allows for the prescription of adequate treatment that can significantly improve the quality of life and restore energy. Treatment can range from dietary correction and hormone therapy to specific medications aimed at eliminating the underlying cause.

Sources

1. [1] Protein energy wasting; what is it and what can we do to prevent it? https://pubmed.ncbi.nlm.nih.gov/31834488/
2. [2] Prolonged coma and cerebral oedema in a patient with an ATP1A2 variant. https://pubmed.ncbi.nlm.nih.gov/41290403/
3. [3] Common Etiologies of Upper Extremity Spasticity. https://pubmed.ncbi.nlm.nih.gov/30286958/
4. [4] Diagnosis and Management of Central Diabetes Insipidus in Adults. https://pubmed.ncbi.nlm.nih.gov/35771962/
5. [5] Thyroid Disease Spectrum in the Emergency Department. https://pubmed.ncbi.nlm.nih.gov/33005521/
6. [6] Association between atrial fibrillation and systemic inflammation with muscle mass and strength trajectories in old age. https://pubmed.ncbi.nlm.nih.gov/42337156/
7. [8] Introduction to the special issue entitled 'Heart failure management of the elderly patient: focus on frailty, sarcopenia, cachexia, and dementia'. https://pubmed.ncbi.nlm.nih.gov/31885503/

The information provided in this article is for reference purposes only and cannot replace professional medical advice. Always consult a specialist for diagnostics and treatment.