The differential diagnosis for fatigue is broad and can be challenging to limit during an initial assessment. Lifestyle factors, medical conditions, medication use, and environmental exposure can cause fatigue. Pathologic fatigue is a subtype of fatigue caused by an underlying medical condition. A thorough patient history, physical exam, and diagnostic evaluation can help to narrow the differential to identify the underlying cause of fatigue. This article will discuss ten medical conditions to consider when constructing a fatigue differential.

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What is Fatigue?

Fatigue is the term used to describe tiredness and exhaustion. Physiologic fatigue is a reaction to intense and prolonged activity or an imbalance in daily lifestyle; it is considered normal, does not affect activities of daily living, and is relieved with rest. An underlying medical condition causes pathologic, or secondary, fatigue; it typically disrupts the quality of life and does not resolve with rest. Fatigue can be further distinguished based on duration. Acute fatigue lasts less than six months, whereas chronic fatigue persists for six months or longer.

Fatigue Symptoms

The word fatigue is often used to describe different sensations. Patients reporting fatigue usually mean one of the following (1):

• Lack of energy: a subjective lack of physical or mental energy during the day
• Drowsiness: the inability to maintain wakefulness during the day
• Weakness: a lack of mental strength unrelated to cognitive function

Fatigue is also commonly accompanied by other symptoms, such as changes in mood, difficulty concentrating, low motivation, joint/muscle pain, and weakness.

Top 10 Differential Diagnoses for Fatigue

Fatigue can be caused by a wide range of conditions, so the differential diagnosis can be quite extensive. Here are some common differential diagnoses for fatigue:

Anemia

Anemia is a hematologic condition defined by decreased circulating red blood cells or decreased hemoglobin concentration, which reduces the body's capacity to distribute oxygen to critical tissues throughout the body. The two most common causes of anemia are iron deficiency and chronic inflammation. Anemias of different origins share many of the same symptoms due to poor oxygenation. Along with fatigue, anemia commonly presents with symptoms like weakness, pale skin, irregular heartbeat, shortness of breath, dizziness, chest pain, cold extremities, and headache. (2)

Sleep Disorders

Up to 80% of patients with fatigue have an underlying sleep disorder, commonly insomnia or obstructive sleep apnea (OSA).

Insomnia, the most common sleep disorder, involves the disruption of initiation and/or maintenance of sleep at least three nights weekly for at least three months. Symptoms of daytime fatigue, mood changes, and poor memory/concentration interfere with daytime functioning in 10-15% of people with insomnia. (5)

Sleep apnea affects up to 15% of middle-aged adults and more than 20% of older adults. OSA is caused by a collapse of the airways during sleep, resulting in repetitive episodes of interrupted breathing. OSA risk increases with obesity, age, and male gender. Common symptoms indicative of OSA include excessive daytime sleepiness, loud snoring, observed episodes of stopped breathing during sleep, and abrupt awakening during the night with gasping or choking. (5, 6)

Depression

Depression is a mood disorder affecting 25 million American adolescents and adults annually. It is characterized by changes in how you feel, think, and handle daily activities. Different types of depression include major depression, dysthymia, perinatal depression, seasonal affective disorder (SAD), and depression with symptoms of psychosis.

Common mental symptoms of depression include sadness, irritability, restlessness, and anxiety; loss of interest; difficult concentration; feelings of worthlessness, guilt, and helplessness; and suicidal ideation. Physical symptoms of depression can include fatigue, difficulty sleeping, changes in appetite and body weight, and body pain. (3)

Hypothyroidism

Hypothyroidism, most commonly caused by autoimmune activity against the thyroid gland, results in the underproduction of thyroid hormones. Hypothyroidism results in a hypometabolic state and can cause symptoms in every body system. Classic symptoms of hypothyroidism include fatigue, weight gain, hair loss, cold intolerance, constipation, and depression (4). Subclinical hypothyroidism, the precursor to hypothyroidism defined by elevated TSH hormone with normal T4 and T3 thyroid hormones, can present with the same hypothyroid symptoms.

Diabetes Mellitus

Diabetes mellitus (DM) is a metabolic condition characterized by elevated blood sugar levels. DM has several classifications, including type 1 and type 2. Type 1 DM (T1DM) is the autoimmune destruction of pancreatic cells responsible for producing insulin; this results in low insulin and high blood sugar levels. Type 2 DM (T2DM) is a condition of insulin resistance by which the body's sensitivity to insulin decreases and results in elevated blood sugar. The cause of T2DM is multifactorial but is heavily dependent on lifestyle and dietary factors.

The hallmark triad of DM symptoms includes frequent urination, increased thirst, and increased hunger. Other symptoms may include fatigue, blurred vision, impaired wound healing, recurring infection, and numbness/tingling in the hands and feet.

Infection

Postviral fatigue syndrome is one of the most common causes of chronic fatigue. Persistent viral infections are those in which the virus is not cleared from the host following the acute illness but remains in the body in either a dormant or active state. Inflammatory immune cytokines contribute to the persistence of fatigue in these chronic infections. Epstein-Barr virus (EBV), human herpesvirus 6 (HHV6), human immunodeficiency virus (HIV), hepatitis C virus, and parvovirus B19 are common viral pathogens associated with postinfectious and chronic fatigue.

Lyme disease, a tickborne disease caused by the Borrelia burgdorferi bacteria, is another infection that commonly causes fatigue in both the acute and chronic stages of infection. Fever, chills, headache, muscle and joint pain, swollen lymph nodes, and an erythema migrans rash are all common symptoms of early Lyme disease. Later signs and symptoms of untreated Lyme disease include severe headaches and neck stiffness, chronic rash, musculoskeletal pain and swelling, heart palpitations, dizziness, nerve pain, and facial palsy. (7)

Malabsorption Syndrome

Poor digestion and absorption of critical macro- and micronutrients leading to nutritional and caloric insufficiencies can cause fatigue. Malabsorption syndrome encompasses many gastrointestinal conditions and diseases, including, but not limited to, celiac disease, Crohn's disease, small intestinal bacterial overgrowth (SIBO), exocrine pancreatic insufficiency (EPI), hypochlorhydria, and gallbladder disease.

Gastrointestinal symptoms like indigestion, abdominal pain, bloating, gas, constipation, diarrhea, and fatty stools will clue into malabsorption contributing to fatigue. Micronutrient deficiencies secondary to malabsorption manifest clinically with nutrient-specific symptoms like skin lesions, frequent infection, swelling, bleeding gums, night blindness, and anemia. (8)

Autoimmune Disease

Autoimmune disease develops when the body loses self-tolerance and begins to mount destructive immune responses against its own tissues. Autoimmune diseases are on the rise, affecting more than 23.5 million Americans. There are more than 80 distinct types of autoimmune diseases, including celiac disease, Hashimoto's thyroiditis, Graves' disease, multiple sclerosis (MS), rheumatoid arthritis (RA), Sjögren's syndrome, systemic lupus erythematosus (SLE), and T1DM. Symptoms of autoimmune disease depend on the specific type present but may include fatigue, joint/muscle pain and swelling, dizziness, skin rashes, abdominal pain, recurring fever, and swollen lymph nodes. (9)

Congestive Heart Failure

Congestive heart failure (CHF) is a type of heart disease in which a weakened heart loses the ability to pump sufficient blood to meet the body's nutrient and oxygen requirements. CHF affects 6.2 million people in the United States. The most common cause of CHF is coronary artery disease. High cholesterol, hypertension, diabetes, and poor diet/lifestyle can increase the risk of developing CHF. Fatigue, shortness of breath, arrhythmia, and lower extremity edema indicate CHF. (10)

Addison Disease

Addison's disease, or primary adrenal insufficiency, is an autoimmune condition that damages the adrenal cortex, leading to insufficient cortisol, aldosterone, and androgen hormone production. It is a rare condition but can be life-threatening in cases of adrenal crisis, characterized by sudden, severe pain in the low back, abdomen, and legs; vomiting and diarrhea; weakness; confusion; and loss of consciousness. Patients with Addison's disease present with fatigue, low blood sugar, generalized weakness, weight loss, dizziness, and hyperpigmented skin. (11)

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Functional Medicine Labs to Test for Fatigue Patients

Complete Blood Count (CBC)

A CBC is a panel that measures blood cell markers to assess overall health and screen for many health conditions. Shifts in red blood cells, white blood cells, and platelets can indicate anemia, chronic and acute infections, inflammation, and nutrient deficiencies contributing to fatigue.

Comprehensive Metabolic Panel (CMP)

A CMP measures blood sugar, electrolytes, pH, and markers of kidney, liver, and gallbladder function. Many medical conditions can lead to deviations in normal CMP lab values; abnormal values and patterns can rule in or out fatigue-inducing conditions. For example, high blood sugar may indicate diabetes, whereas low sodium, high potassium, and low blood sugar is a classic lab pattern associated with Addison's disease.

Hemoglobin A1c (HbA1c)

HbA1c is a 3-month average of blood sugar used as the designated marker to diagnose and monitor diabetes.

In patients with T2DM, a comprehensive diabetes panel can provide more insight into insulin sensitivity and daily control of blood sugar.

T1DM is associated with autoantibodies that impair endogenous insulin secretion. The presence of GAD-65, islet cell, and insulin antibodies predicts T1DM in patients without hyperglycemia and can differentiate between type 1 and type 2 DM in patients with diabetes.

Thyroid Panel

A comprehensive thyroid panel measures multiple hormones involved in thyroid hormone production and processing, and thyroid antibodies associated with Hashimoto's hypothyroidism. Elevated TSH with low thyroid hormone is diagnostic for hypothyroidism. A comprehensive panel can be more beneficial than a basic TSH screening test because it evaluates how the brain and thyroid interact to produce thyroid hormones and how the peripheral tissues can utilize them. Factors interfering at any level of this axis can contribute to hypothyroid-like symptoms.

Cortisol

Diagnosis of adrenal insufficiency is based on low serum cortisol levels. Most endocrinologists confirm the diagnosis with a low serum cortisol level during an adrenocorticotropin (ACTH) stimulation test.

Salivary and urinary cortisol testing are not the preferred cortisol measurement method when ruling out Addison's disease. However, these tests are available and can be utilized in a more functional capacity in the absence of Addison's and in the presence of adrenal dysregulation (commonly seen during chronic stress).

Infectious Panel

Antibody blood testing is often ordered in conjunction with a CBC when screening for infectious causes of fatigue. Generally, infections found in the acute state will elevate white blood cells (WBC), whereas depressed WBC counts are commonly seen in chronic infection states. Antibody tests commonly ordered in the context of fatigue include combo viral, Lyme, HIV, and hepatitis C screenings.

Autoimmune Panel

An antinuclear antibody (ANA) test with reflex is the conventional screening recommendation for autoimmune disease. If ANA is positive, the lab will assess for the presence of specific antibodies associated with the most common autoimmune disorders.

The Cyrex Array 5 panel is an autoimmune reactivity screen that measures IgA and IgG antibodies, which increases testing sensitivity, to various tissue types. It can benefit patients at risk of Addison's disease, chronic fatigue syndrome, diabetes, fibromyalgia, autoimmune thyroiditis, inflammatory bowel disease, lupus, RA, and other autoimmune-related diseases.

Comprehensive Stool Test

Patients with fatigue and gastrointestinal symptoms will likely benefit from a comprehensive stool analysis, which measures markers of digestion and absorption, intestinal inflammation, and the gut microbiome. It is a good overview of digestive health and function, and abnormal results help to pinpoint underlying causes of digestive dysfunction to guide next-step diagnostic testing and treatment recommendations.

Other Lab Tests to Check

GAD-7 and PHQ-9 screening questionnaires objectify and assess the severity of anxiety and depression. These questionnaires help screen for mood disorders and monitor treatment efficacy.

A sleep study is considered the diagnostic gold standard for most sleep disorders. Referral for sleep study should be considered for patients with signs of and risk factors for a sleep disorder.

A cardiologist referral may also benefit patients with risk factors for heart disease and CHF. A cardiology evaluation may include further blood work, stress testing, and heart imaging.

Integrative Medicine Treatment for Fatigue

The treatment of fatigue relies on addressing and treating its underlying cause. The treatment recommendations discussed below will be focused on general lifestyle recommendations that can benefit anyone with fatigue or patients with fatigue of unknown cause to support energy levels and quality of life.

Nutrition for Fatigue

Research suggests a link between systemic inflammation and chronic disease-related fatigue. A large pool of available data indicates that anti-inflammatory, balanced diets improve fatigue symptoms. Anti-inflammatory diets are generally defined as those rich in vegetables (high in fiber and anti-inflammatory polyphenols) and omega-3 fatty acids.

High-carbohydrate and sugar diets can cause fluctuations in blood sugar in patients with and without diabetes. Hyper- and hypoglycemic states ("dysglycemia") can both cause fatigue. Incorporating adequate protein and fat in meals, especially when eating carbohydrates, positively affects the glycemic response and helps to balance blood sugar throughout the day.

Supplements & Herbs for Fatigue

Adaptogenic herbs support the body's ability to cope with stress and improve energy levels, stress, and sleep quality. Commonly recommended adaptogens include ashwagandha, Rhodiola, ginseng, and Schisandra.

Nervine herbs support the nervous system and can relieve muscle tension, ruminating thoughts, and other symptoms associated with anxious states. Nervines taken at bedtime can promote restful sleep. Popular nervines include skullcap, oat, valerian, and hops.

Glutathione is a potent antioxidant that supports the immune system, promotes healthy detoxification pathways, and reduces systemic inflammation. Glutathione enhances cardiovascular health and lung function, improving blood flow and oxygenation capacity. Chronic inflammation is associated with fatigue; supplementing glutathione to reduce inflammation can promote enhanced energy levels.

Mitochondria health and function are imperative to optimal energy production. Nutrients, including omega-3 fatty acids, vitamin C, zinc, B vitamins, magnesium, and CoQ10, are important in reducing oxidative damage within the mitochondria and supporting their energy metabolism capacity.

Lifestyle Modifications for Fatigue

Moderate-intensity exercise can result in small-to-moderate improvements in fatigue, energy, and vitality. Additionally, exercise improves underlying conditions commonly contributing to fatigue, such as diabetes and depression.

Limit caffeine intake. Although a stimulant, increased consumption of caffeine can actually exacerbate fatigue. Interference with sleep, caffeine tolerance, promotion of dehydration and dysglycemia, and adenosine surges related to caffeine intake can cause sleepiness and muscle fatigue.

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Summary

The medical evaluation of fatigue can be complex, given the many factors predisposing a person to feel tired. Successful treatment of fatigue relies on the accurate diagnosis of the underlying mechanism; therefore, creating a robust differential diagnosis is an essential aspect of fatigue evaluation. This article discussed ten medical conditions that should be considered as underlying causes of fatigue. Patient history, physical exam, and laboratory findings will guide the diagnostic process. Good management of the root cause is the key to successfully treating fatigue. While the root cause is being addressed, energy levels can be improved and managed through lifestyle modifications, natural herbs, and supplements that holistically tonify the body, support energy production, and reduce inflammation. Check out the Rupa Magazine website for functional protocols specific to medical conditions discussed in this article.