In addition to today’s resource, please review:

Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Clin Med. 2020 Aug 5;9(8):2531. doi: 10.3390/jcm9082531.

There are  83 similar articles in PubMed.

The above article has been cited by 15 articles in PubMed.

Abstract

In this study we set out to define the characteristics of autonomic subgroups of patients with Chronic Fatigue Syndrome (CFS). The study included 131 patients with CFS (Fukuda criteria). Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Fatigue Impact Scale, Fatigue Severity Scale, Epworth Sleepiness Scales, the self-reported Composite Autonomic Symptom Scale. Autonomic parameters were measured at rest with a Task Force Monitor (CNS Systems) and arterial stiffness using an Arteriograph (TensioMed Kft.). Principal axis factor analysis yielded four factors: fatigue, subjective and objective autonomic dysfunction and arterial stiffness. Using cluster analyses, these factors were grouped in four autonomic profiles: 34% of patients had sympathetic symptoms with dysautonomia, 5% sympathetic alone, 21% parasympathetic and 40% had issues with sympathovagal balance. Those with a sympathetic-dysautonomia phenotype were associated with more severe disease, reported greater subjective autonomic symptoms with sympathetic over-modulation and had the lowest quality of life. The highest quality of life was observed in the balance subtype where subjects were the youngest, had lower levels of fatigue and the lowest values for arterial stiffness. Future studies will aim to design autonomic profile-specific treatment interventions to determine links between autonomic phenotypes CFS and a specific treatment.

Keywords: autonomic, chronic fatigue, quality of life

Today, I review, link to, and excerpt from The Curbsiders’ #213 Fatigue for Primary Care with Nina Mingioni MD.*

*Mingioni N, Abrams HR, Williams PN, Watto MF. “#213 Fatigue for Primary Care with Nina Mingioni MD”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list. Air date May 11, 2020.

All that follows is from the above resource.

Listen as our esteemed guest Dr. Nina Mingioni walks us through her approach to fatigue, from differential diagnosis, to the evidence behind physical exam, laboratory workup, and beyond!

We are excited to announce that the Curbsiders are now partnering with VCU Health Continuing Education to offer continuing education credits for physicians and other healthcare professionals. Check out curbsiders.vcuhealth.org/ for more information.

Time Stamps

• 00:00 Intro, disclaimer, guest bio and a bad pun
• 03:00 Guest one-liner
• 07:10 Case from Kashlak, Defining fatigue; Taking a general history
• 11:36 Most common causes of fatigue and how to elicit them from the history
• 20:39 Physical exam for fatigue; Medications that cause fatigue;
• 25:25 Exam findings and LRs for anemia; Sleep apnea
• 30:55 Lab workup for fatigue; Expanded testing: Ferritin, Vitamins, EBV, Rheumatologic diseases, Celiac disease, Lyme
• 47:55 Spiel to the patient when no answer is found
• 51:14 Other diagnoses to consider: Fibromyalgia, Myalgic Encephalomyelitis
• 55:09 Take home points and Outro

Fatigue Pearls

“Fatigue” can mean different things to different people! Try to differentiate between “sleepiness,” “weakness,” “lack of energy,” “decreased exercise tolerance,” “feeling down,” and “dyspnea on exertion.”

Anemia, depression, hypothyroidism, sleep apnea, cardiopulmonary disease, and medication/supplement effects are common causes of fatigue. Especially watch out for beta blockers and antihistamines!

Conjunctival rim pallor (outer rim same color as inner rim) has a likelihood ratio of >15 for anemia (McGee 2017). Pica also has an odds ratio of 2.4 for iron deficiency anemia and your patients may not mention it if you don’t ask about craving ice/starch specifically.

As a basic workup for fatigue, Dr. Mingioni recommends a CBC, BMP, LFTs, TSH, and age-appropriate screening including cancer, HIV, and Hepatitis C.

Consider checking calcium with your BMP (if not included) to assess for hyperparathyroidism as a cause of fatigue!

Ferritin may be a useful test if you’re concerned for iron deficiency as a cause of fatigue; supplementation even in patients who aren’t anemic but do have low ferritin has been shown to improve symptoms.

Expanded laboratory workup (e.g. Vit D, Vit B12, EBV, rheumatologic diseases panel, Celiac disease,  and Lyme) is generally low yield and should only be sent based on clinical suspicion.

Fatigue Notes 

Defining Fatigue & Common Causes

“Fatigue” can mean many different things to different people. A good history is key to differentiating between “sleepiness,” “weakness,” “lack of energy,” “decreased exercise tolerance,” “feeling down,” and “dyspnea on exertion” that patients might experience with common causes of fatigue.

Of note, a definitive cause of fatigue can sometimes be difficult to find. Dr. Mingioni stresses the importance of your rapport with the patient. She emphasizes up-front that she will continue to work with them on diagnosis and symptom management even if a cause is not found initially.

Most Common (Identifiable) Causes of Fatigue

Unfortunately, there are no studies that truly identify the frequency of each cause of fatigue in the general population. However, Dr. Mingioni shares her illness scripts for several common causes of fatigue.

Anemia

“Fatigue and…” dyspnea, dizziness, and decreased exercise tolerance. More prevalent in younger women and people who menstruate, or in those at risk of malabsorption.

Sleep Disorders and Sleep Apnea

Fatigue manifesting as sleepiness, including sleep apnea, insufficient sleep, and sleep latency disorders. May be more common in patients with obesity and retrognathia.

Kashlak Pearl: Dr Mingioni notes that men with small jaws sometimes grow beards or goatees! Dr Williams concurs : )

Depression

“Fatigue and…” anhedonia, depressed mood. Depressed people are more likely to experience fatigue, and people with fatigue are more likely to have depression. Specifically, ask about insomnia and poor concentration (Corfield 2016).

*Patient Health Questionnaire-9 (PHQ-9) from The National HIV Curriculum, accessed 3-24-2025.

The PHQ-9 is a multipurpose instrument for screening, diagnosing, monitoring and measuring the severity of depression.

**The National HIV Curriculum is an AIDS Education and Training Center Program and led by the University of Washington.

Hypothyroidism

“Fatigue and…” weight gain, edema, dry skin, goiter, or family history of endocrinopathy.

Cardiac Disease

While fatigue is unlikely to occur in isolation in acute coronary syndrome (ACS), approximately 60% of all patients with unstable angina report unusual fatigue. (Kreatsoulas 2013) Cardiac disease may be a cause of dyspnea on exertion and decreased exercise tolerance that patients describe as fatigue.

Medication/Supplement Effects

Consider fatigue as a sequela of medications or supplements particularly in patients taking beta blockers, antihistamines, narcotics, muscle relaxants, sedative/hypnotics, benzodiazepines, gabapentin, venlafaxine, and tricyclic antidepressants. Fatigue-causing supplements to be aware of include St. John’s Wort, Valerian Root, and Saw Palmetto. (Posadzki 2013) For medications, consider whether high starting doses as a cause or consider medication-supplement interaction.

History & Physical Exam Pearls for Fatigue

Review of Systems for Fatigue

General Fatigue ROS

Dr. Mingioni recommends organizing your fatigue review of systems by time of day, beginning with sleep initiation. She asks questions about sleep initiation and maintenance, then moves into questions about awakening, energy, and anhedonia. For the daytime portion she asks about energy, exertion and dyspnea on exertion, and then daytime sleepiness and naps. Non-time oriented questions she always asks are weight changes and edema (hypothyroid symptoms), abnormal bleeding or pica (anemia), bowel changes (malignancy), and dyspnea/edema (cardiopulmonary).

Anemia

Pica is associated with a 2.4 times greater odds of iron deficiency anemia. (Miao 2014) Dr. Mingioni recommends specifically asking about abnormal cravings, including ice and starch, because patients may otherwise not bring this up.

PHQ-9

Dr. Mingioni recommends asking your patient to complete a PHQ-9 if there is a clinical concern for depression associated with fatigue.

Physical Exam Pearls for Fatigue

While physical exam may have limited sensitivity for causes of isolated fatigue, Dr. Mingioni assesses vital signs, cardiopulmonary exam, abdominal exam, thyroid exam, and ENT exam with Mallampati score in all patients with fatigue. She recommends a muscle strength exam for patients with weakness. Conjunctival rim pallor (outer rim same color as inner rim) has a positive likelihood ratio of >15 for anemia! (McGee 2017)

Laboratory Workup for Fatigue

General Workup

There are unfortunately few recent evidence-based guidelines for high value workup of fatigue. If there is no clear syndrome from history and physical exam, Dr. Mingioni recommends a CBC, BMP (with Calcium), LFTs, and TSH. Yield is generally low. (Valdini 1989, Lane 1990) She also recommends ensuring that patients are up to date on all age appropriate screening, including cancer screening, HIV screening, and Hepatitis C screening if born between 1945-65.

Specific Considerations

Ferritin

Dr. Mingioni recommends checking a ferritin if there is clinical concern for anemia as a cause of fatigue. In non-anemic menstruating women with unexplained fatigue and low ferritin levels iron supplementation improved fatigue. (Krayenbuehl 2011, Vaucher 2012)

ESR/CRP

Elevations of ESR and CRP are nonspecific and don’t necessarily add diagnostic value in patients for whom you already have a moderate/high suspicion for inflammatory causes of fatigue. More specific testing will be needed for diagnosis.  (Bray 2016)

Vitamin D

Vitamin D may be associated with fatigue in older adults, but it is not associated with systemic exertion intolerance disease (also known as myalgic encephalomyelitis/chronic fatigue syndrome). (Pennisi 2019, Earl 2017) It may be appropriate to order if a patient has muscular weakness.

Vitamin B12

Isolated fatigue is not defined as a neuropsychiatric symptom of Vitamin B12 deficiency. However, in elderly patients or patients who are prone to malabsorption, Dr. Mingioni may check methylmalonic acid (MMA). (Pennypacker 1992, Hunt 2014)

T3/T4

Because TSH is part of the routine workup for fatigue, the added diagnostic value of T3/T4 is limited to diagnosing secondary hypothyroidism, which is relatively rare and more commonly occurs with other symptoms of panhypopituitarism. (Persani 2012) Dr. Mingioni does not recommend checking T3/T4.

EBV Titers

Fatigue may be a long-term sequelae of infectious mononucleosis secondary to EBV, but EBV titers are non-specific and may not provide major diagnostic or therapeutic value.

Lyme Serologies

Like EBV, acute Lyme infection can be associated with fatigue during and after disease recovery. Chronic Lyme disease is a poorly defined syndrome that often is defined as including chronic pain, fatigue, and neurocognitive symptoms. While this syndrome is real and creates a significant burden for patients, it is not consistent with the symptoms of neuroborreliosis and is not currently believed to be caused by Borrelia burgdorferi infection; Dr. Mingioni does not recommend Lyme serologies for routine workup of isolated fatigue. (Lantos 2015)

Celiac Disease Testing

Fatigue is a common symptom of celiac disease, but rarely is the sole presenting symptom. (Skjellerudsveen 2019) Dr. Mingioni does not recommend testing for celiac disease without other symptoms present.

Addressing Other Concerns

Occult Malignancy

While following up on routine age appropriate cancer screening and assessing for other symptoms of occult malignancy is important, Dr. Mingioni points out that there is no literature to support isolated fatigue as a sole presenting symptom of malignancy.

Systemic Exertion Intolerance Disease (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)

Systemic Exertion Intolerance Disease (SEID), also known as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), is a syndrome of fatigue that requires two of the following three symptoms: 6 months of profound fatigue with impaired ability to perform ADLs, post-exertional malaise, and unrefreshing sleep; and at least one of the two following manifestations: cognitive impairment and orthostatic intolerance. (IOM 2015) It should be considered in patients with profound fatigue lasting > 6 months.

References

1. Corfield EC, Martin NG, Nyholt DR. Co-occurrence and symptomatology of fatigue and depression. Compr Psychiatry. 2016. [https://www.ncbi.nlm.nih.gov/pubmed/27567301]
2. Kreatsoulas C et. al. Reconstructing Angina: Cardiac Symptoms Are the Same in Women and Men. JAMA Intern Med. 2013 [https://www.ncbi.nlm.nih.gov/pubmed/23567974]
3. Posadzki P, Watson LK, Ernst E. Adverse effects of herbal medicines: an overview of systematic reviews. Clin Med (Lond). 2013. [https://www.ncbi.nlm.nih.gov/pubmed/23472485]
4. Miao D, Young SL, Golden CD. A meta-analysis of pica and micronutrient status. Am J Hum Biol. 2015. [https://www.ncbi.nlm.nih.gov/pubmed/25156147]
5. McGee S. Evidence-Based Physical Diagnosis. 3rd ed. Philadelphia PA: Saunders; 2012
6. Valdini A, Steinhardt S, Feldman E. Usefulness of a standard battery of laboratory tests in investigating chronic fatigue in adults. Fam Pract. 1989. [https://pubmed.ncbi.nlm.nih.gov/2632306/]
7. Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990 [https://pubmed.ncbi.nlm.nih.gov/2337122/]
8. Waldvogel S, Pedrazzini B, Vaucher P, et al. Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trial. BMC Med. 2012 [https://pubmed.ncbi.nlm.nih.gov/22272750]
9. Bray C, Bell LN, Liang H, et al. Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine. WMJ. 2016. [https://pubmed.ncbi.nlm.nih.gov/29094869]
10. Pennisi M, Malaguarnera G, Di Bartolo G, et al. Decrease in Serum Vitamin D Level of Older Patients with Fatigue. Nutrients. 2019. [https://pubmed.ncbi.nlm.nih.gov/31635199]
11. Earl KE, Sakellariou GK, Sinclair M, et al. Vitamin D status in chronic fatigue syndrome/myalgic encephalomyelitis: a cohort study from the North-West of England. BMJ Open. 2017. [https://pubmed.ncbi.nlm.nih.gov/29118054]
12. Pennypacker LC, Allen RH, Kelly JP, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc. 1992 [https://pubmed.ncbi.nlm.nih.gov/1447433]
13. Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014. [https://pubmed.ncbi.nlm.nih.gov/25189324]
14. Persani L. Clinical review: Central hypothyroidism: pathogenic, diagnostic, and therapeutic challenges. J Clin Endocrinol Metab. 2012;97(9):3068-3078. [https://pubmed.ncbi.nlm.nih.gov/22851492]
15. Lantos PM. Chronic Lyme disease. Infect Dis Clin North Am. 2015. [https://pubmed.ncbi.nlm.nih.gov/25999227]
16. Skjellerudsveen BM, Omdal R, Grimstad T. Fatigue in celiac disease: A review of the literature. JGH Open. 2019. [https://pubmed.ncbi.nlm.nih.gov/31276043]
17. Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Report Guide for Clinicians. IOM. 2015. [https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf]

Comments

For a resource relevant to the comment below, please see Autonomic Phenotypes in Chronic Fatigue Syndrome (CFS) Are Associated with Illness Severity: A Cluster Analysis [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. J Clin Med. 2020 Aug 5;9(8):2531. doi: 10.3390/jcm9082531.

There are  83 similar articles in PubMed.

The above article has been cited by 15 articles in PubMed.

May 18, 2020, 8:45pmLi H. writes:

Excellent episode! And thank you for your commitment to your patients during what can often be a very frustrating process, Dr. Mingioni. One question… Do you ever consider dysautonomia in your workup and if so, at what point? My 20 y.o. daughter struggled with fatigue, exhaustion after exercise, and vague digestive issues for close to 18 months before being diagnosed with POTS, a form of dysautonomia. It was an internist at a major university that does research on POTS that took my daughter’s vitals while standing and noticed this. She was able to get referred to the right neurologist who officially diagnosed it and treated her with diet changes in addition to medication.. it has made a huge difference in reducing her fatigue.