Fatigue Follow-up

Abstract & Commentary

By Allan J. Wilke, MD, MA, Professor and Chair, Department of Integrative Medicine, Ross University (Bahamas) Limited, Freeport, Grand Bahama, The Bahamas. Dr. Wilke reports no financial relationship to this field of study.

Synopsis: After 1 year, fewer than half of patients presenting with fatigue will have a diagnosis.

Source: Nijrolder I, et al. Diagnoses during follow-up of patients presenting with fatigue in primary care. CMAJ 2009;181:683-687.

The symptom of fatigue can be a manifestation of many diverse diseases. A short list of systems (and conditions) includes cardiac (heart failure), hematologic (anemia), neoplastic (leukemia), paraneoplastic (Eaton-Lambert syndrome), rheumatologic (scleroderma), respiratory (chronic obstructive lung disease), metabolic (diabetes mellitus), endocrinologic (hypothyroidism), psychiatric (depression), and reproductive (pregnancy). These researchers from the Netherlands performed a cohort observational study that followed 571 adults from 147 general practices who presented for the first time with fatigue to answer the question, "What diagnoses reveal themselves one year after presenting with fatigue?" Exclusion criteria included a presentation with "malaise," pregnancy or recent childbirth, and recent chemotherapy or radiotherapy. Subjects averaged 43 years of age and were predominantly female (74%). Subjects were queried about symptoms periodically after presentation. The researchers went back to the subjects' medical records to see what chronic illnesses were present at the start of the study and what diagnoses their physicians made in the ensuing year. Of the 571 subjects, 268 had at least one diagnosis that might be associated with fatigue.

As expected, no one diagnosis stood out and most were signs or symptoms. Some of the more common ones were various infections, joint or back problems, nervous strain, depression, anxiety, and abdominal pain. Only 8% had actual pathologic diagnoses. Anemia and hypothyroidism were the most common. The subjects' questionnaires were more revealing and discordant with their medical records, with reports of depression (24% vs 5%), worry (61% vs 4%), and sleep problems (65% vs 2%). Chronic illnesses that could reasonably be associated with fatigue appeared in 58 of 539 charts, including respiratory diseases, diabetes mellitus, and malignancy. Slightly more than half of the patients (52%) expected their physician would find a cause of the fatigue, but the vast majority (91%) were satisfied with the physician's management.


The chief weakness of this study was its lack of a structured protocol for physical examination and work-up of fatigue. One source recommends CBC, sedimentation rate, chemistry panel, VDRL, urinalysis including analysis for myoglobin, CPK, LDH, AST, urine creatine and creatinine, thyroid profile, serum cortisol, and 24-hour urine aldosterone.1 Cost containment be damned. In 2007, Ponka and Kirlew published their "top 10" differential diagnosis list for fatigue: (in order) fatigue not yet diagnosed, viral illness, depression, anemia, anxiety/stress, sinusitis, congestive heart failure, medication side effect, influenza, and diabetes mellitus.2 This would suggest that a good history and physical and a limited lab work-up would suffice.

There is good news and bad news in this paper. The good news is there were few serious illnesses encountered. The bad news is the poor job these general practitioners did in documenting fairly common psychological problems associated with fatigue. Did they know their patients were suffering from depression, worry, and sleep disturbance, or did they choose not to record this in the chart? Worse yet, did they miss the connection between these problems and fatigue? The nature of this study does not allow for claims of causation (e.g., does depression cause fatigue or does fatigue cause depression?).

In a related development, researchers recently reported an association between chronic fatigue syndrome (CFS) and a retrovirus, xenotropic murine leukemia virus-related virus, which was detected in WBCs from 67% of CFS patients, but only 4% of healthy controls.3

Fatigue is a common reason for patients to visit a primary care physician. They deserve thorough office evaluation and laboratory investigations as indicated. If, after initial evaluation, nothing points to an organic cause, time would be better spent seeking and ameliorating a psychiatric source of distress.


1. Collins RD. Algorithmic Diagnosis of Symptoms and Signs. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.

2. Ponka D, Kirlew M. Top 10 differential diagnoses in family medicine: Fatigue. Can Fam Physician 2007;53:892.

3. Lombardi VC, et al. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009;326:585.