One of the most prevalent medical complaints in primary care is fatigue, estimated to arise in up to 1 in 5 consultations. There appears to be no consensus on a definition of fatigue, which is curious given how common the condition is.

When patients indicate they experience fatigue, they may be referring to a lack of energy/libido, listlessness, an excessive amount of sleep or lack thereof, or feelings of depression. Colloquially, many patients would describe their fatigue as “running on empty.” 

When a patient chooses to raise concerns about fatigue in a primary care setting, it usually indicates that the patient’s typical coping strategy has failed. In other words, a patient describing a precipitous drop in energy levels at work likely means that their go-to mechanism for rest and recuperation no longer yields the tangible benefits they expect, causing the lack of energy to last for longer than expected. 

If fatigue persists for more than 6 months, it is usually classified as “chronic fatigue.” Studies indicate that untreated fatigue can compromise quality of life; for example, a patient may find their job performance slipping, which can generate anxiety and worsen feelings of tiredness. Chronic fatigue is also associated with an increased rate of accidents. 

It is always advisable for physicians to take a thorough history of what a patient describes as “fatigue” to get to the root source of the problem. If, for example, the problem is primarily a mental health issue, the patient may be referred to psychiatric services. If the fatigue is the result of a medical diagnosis, the effective treatment of the underlying condition can alleviate symptoms to a considerable degree.

Sometimes, fatigue can point to an undiagnosed condition, such as anemia or thyroid dysfunction. Both these conditions can readily be treated once diagnosed. Fatigue is also a common complaint in cancer, affecting approximately 60% of patients; some studies indicate that fatigue is among the most distressing symptoms in individuals with cancer. 

Fatigue and Paroxysmal Nocturnal Hemoglobinuria 

Another condition which can lead to reports of fatigue is paroxysmal nocturnal hemoglobinuria (PNH), a rare disorder characterized by chronic hemolysis and resulting anemia. Patients with this condition require lifelong medical treatment, with the risk that symptoms may flare up periodically. 

What are the primary concerns of patients with this condition? In the Journal of Blood Medicine, Fattizzo and colleagues sought to explore this question and found that many practitioners do not typically use questionnaires or a fixed format to understand patients’ concerns about the impact of this disease on their quality of life. 

“Clinicians usually evaluate patients’ [quality of life] by simply asking them “how are you” during routine visits,” they observed. “The ability to elicit [patient-reported outcomes] varies between professionals.” 

Read more about PNH etiology 

They hence proposed the use of structured surveys in clinical settings. According to their investigation, fatigue is among the most frequently reported symptoms in PNH; patients often describe feelings of tiredness stemming from the disease itself and the struggle to manage the condition and attend follow-ups in daily life. 

A key reason fatigue is so prevalent among individuals with PNH is that the current treatment regime for this condition is not curative (with the exception of allogeneic bone marrow transplantation, which is rarely performed). For example, eculizumab, a complement inhibitor used to manage PNH, can prevent complement-mediated destruction but cannot eliminate PNH clones.

In addition, PNH complications can often be severe. Patients with PNH are always at risk of thrombosis, and this can occur in atypical locations, such as the cerebral, mesenteric, and renal veins. Studies suggest that lifestyle factors such as cigarette smoking, obesity, and diabetes may raise thrombotic risk. 

“Not only the occurrence but even the fear of PNH complications further impact [quality of life] and may lead to a feeling of ‘life limitation’ and ‘frailty’ in these patients,” Fattizzo et al wrote.

Strategies for Alleviating Symptoms

What can be done to alleviate symptoms of fatigue in patients with PNH? A good place to start is to ensure that individuals demonstrating symptoms of this condition are thoroughly investigated during diagnostic workup. A timely diagnosis and subsequent initiation of treatment can prevent the disease from worsening to an intolerable degree. 

In order to eliminate the risk of complications and flare-ups, it would of course be ideal for future therapeutic solutions to be curative. While this may be unachievable in the short-to-medium term, some therapies under investigation demonstrate promise. For example, pegcetacoplan, a C3 inhibitor, has been shown to significantly improve patients’ quality of life and symptoms of fatigue. Danicopan, an oral factor D inhibitor, has shown similar efficacy, particularly when used with eculizumab. 

Read more about PNH treatment 

Another way to combat fatigue in PNH is to ensure that surveys quantifying quality of life are regularly used during primary care consultations, allowing physicians to ask pertinent questions in an orderly, comprehensive manner. This then opens up the space for honest dialogue and careful follow-up.

“The management of patients with fatigue as their main symptom is characterized by . . . empathetic patient counseling, expectant observation, and regularly scheduled follow-up,” Maisel and colleagues wrote in Deutsches Ärzteblatt International. 


Maisel P, Baum E, Donner-Banzhoff N. Fatigue as the chief complaint — epidemiology, causes, diagnosis, and treatmentDtsch Arztebl Int. 2021;118(33-34):566-576. doi:10.3238/arztebl.m2021.0192

Fattizzo B, Cavallaro F, Oliva EN, Barcellini W. Managing fatigue in patients with paroxysmal nocturnal hemoglobinuria: a patient-focused perspectiveJ Blood Med. 2022;13:327-335. doi:10.2147/JBM.S339660