5.8 Common errors and fallacies
Pathological laboratory values are hastily accepted as a sufficient explanation.
In a study of 220 patients complaining of fatigue [28], four cases were diagnosed as subclinical hypothyroidism.
subclinical hypothyroidism. Of these, three could be substituted until normalization of
normalization of TSH, but their fatigue had not improved!
had not improved! Thus, this was the coincidental coincidence of two common
conditions (fatigue and subclinical hypothyroidism). Consequence: critical evaluation of
subjective condition and abnormal findings in the longitudinal course, restrained use of laboratory
laboratory tests and other further diagnostics.
Aids for Good Medicine www.degam-leitlinien.de67
Physicians first rule out physical causes and only then work on the psychosocial area.
the psychosocial area.
Clear somatic causes are only found in a small proportion of patients or those with primary unexplained causes.
patients with primary unexplained fatigue. An organic clarification process that lasts for weeks
process of organic clarification can, until its conclusion, fixate the conviction in the patient that the
that there is a hidden physical illness as the cause [436].
[436]. This view is very difficult to correct later. Consequence: a psychosocial
psychosocial understanding with the patient at the time of the initial contact; this will be
even in the rare case of a purely somatic explanation of fatigue.
of the doctor-patient relationship, because somatic diseases also have their psychological and social components.
and social components. Patients with excessive daytime sleepiness and proven sleep apnea syndrome
sleep apnea syndrome often also have symptoms of depression [437].
In the case of known chronic diseases, fatigue is hastily related to the disease process itself.
to the disease process itself.
In fact, depression or exhausted mental compensations are,
disturbed sleep, pain, consequences of physical inactivity (deconditioning), thera-
side effects of therapy and interactions between all these factors are at least as important.
These general factors require specific treatment and rehabilitation measures.
bilitation measures. Consequence: apply this guideline consistently to patients with known chronic
known chronic diseases.
Premature labeling
In the case of unspecific disturbances of well-being, which are often accompanied by severe impairment
impairment, the temptation is great for those affected as well as for physicians
to agree hastily on insufficiently substantiated (pseudo) diagnoses. These labels
tions correspond, for example, to biological (iron or vitamin D deficiency, hypotension, hypog- lycemia), environmental
lycemia), environmental (MCS, amalgam exposure, intolerances), infectious (intestinal microbiome, Candida)
(intestinal microbiome, candida) and other hypotheses. What they have in common is that the corresponding
scientifically insufficiently documented or even refuted, not plausible and/or not
plausible and/or not proven in individual cases. However, patients often feel
often feel taken seriously and relieved with such diagnoses. These diagnoses are problematic
problematic if they are one-sidedly somatic or prevent a necessary wait-and-see approach.
of keeping an open mind. Thus they often lead to a narrow perspective for doctors as well as for the patients.
perspective, which disregards complex psychosocial factors and fails to offer appropriate solutions.
psychosocial factors and obstructs appropriate solution options [438], as well as
dangerous courses that can be averted.
Aids for Good Medicine www.degam-leitlinien.de68
Bogus associations and self-fulfilling prophecies
An illusory association, e.g., of low vitamin D levels and fatigue, may arise when physicians, on the basis of
doctors, on the basis of corresponding convictions, increase the number of determinations
of this laboratory value in patients who complain of fatigue; this will
known patients with low vitamin D levels will increasingly be recruited from this group, even though the
although the non-fatigued patients are just as likely to have such a finding.
have such a finding, but it is not detected [139]. Among the patients with
vitamin D deficiency" diagnosed in this way, the "tired" are more frequently represented, since it is more likely to be
They are more likely to be detected, but not because the low level is the cause of fatigue.
The uncritical "experience" thus confirms the view that leads to selective diagnostics,
is confirmed again and again [439]. If vitamin D is then substituted, place-
the vitamin D deficiency theory, as has been shown for latent iron deficiency [132].
iron deficiency [132].
Fig. 3: What to do: Diagnostics negative, fatigue remains?
[diagram page 68]
6 Therapeutic procedure
6.1 Recommendation (modified 2022)
It should be noted that there are often several
causal health problems must be assumed and
and need to be treated.
Recommend-
degree of recommendation
B
Level of
evidence
II
Result
Consensus procedure
13 Yes
0 no
0 abstentions
Strong consensus
Literature reference: [35-38]
For details, see chapters 4.2.12, 5.4.
6.2 Recommendation (modified 2022).
In the case of unexplained fatigue and/or indications of relevant
relevant psychosocial stress, fixed follow-up appointments should be offered.
fixed follow-up appointments should be offered.
Recommend-
degree of recommendation
A
Level of
evidence
III
Result
Consensus process
13 Yes
0 no
0 abstentions
Strong consensus
Literature reference: [39]
https://www.awmf.org/leitlinien/detail/ll/051-001.html
Details see chapter 5.4
6.3 Recommendation (modified 2022)
In the case of substance abuse/harmful use, espe-
especially of tobacco, cannabis or alcohol, a short
a brief intervention and, if necessary, cessation treatment should be offered.
treatment should be offered.
Recommend-
degree of recommendation
A
Level of
evidence
Ia
Result
Consensus procedure
12 Yes
0 no
1 abstentions
Strong consensus
Reference: [40-43]
https://www.awmf.org/leitlinien/detail/ll/038-025.html
https://www.awmf.org/leitlinien/detail/ll/076-001.html
https://www.awmf.org/leitlinien/detail/ll/076-006.html
Details see chapter 6.3
Aids for Good Medicine www.degam-leitlinien.de70
6.4 Recommendation (modified 2022)
The treatment of potentially causative diseases should be optimized.
diseases should be optimized.
Recommend-
degree of recommendation
A
Level of
evidence
Ia
Result
Consensus procedure
12 Yes
0 no
0 abstentions
Strong consensus
Literature reference: [33,44,45]
https://www.leitlinien.de/themen/copd
https://www.leitlinien.de/themen/herzinsuffizienz
https://www.leitlinienprogramm-onkologie.de/leitlinien/supportive-therapie/
Details see chapter 6.4
6.5 Recommendation
A. (modified 2022) In the case of a large number of underlying
underlying disorders or diseases
behavioral therapy and/or symptom
ptom-oriented activating measures improve fatigue and
fatigue and general well-being and should be offered in these cases.
be offered in these cases.
* This does not apply to ME/CFS including ver-
diagnosis.
Recommend-
degree of recommendation
A
Level of
evidence
Ia-IV
Result
Consensus procedure
14 Yes
0 no
2 abstentions
Strong consensus
Reference: [20,46-48]
https://www.nice.org.uk/guidance/ng206
For details, see sections 6.1, 6.3, 6.4. and 5.7.
B. (new 2022) In the case of unexplained fatigue.
behavioral therapy and/or symptom-oriented activating
Activating measures can be offered.
This does not apply to ME/CFS including
diagnosis.* In this case, the individual reaction to the
individual response to these and, if necessary, the
measures are to be adjusted or terminated.
* This does not apply to ME/CFS, including the diagnosis of
diagnosis
C. (New 2022) In ME/CFS, no physical
activations based on the deconditioning
concept should be offered. Attention should be paid to the
Exercise intolerance with varying latency.
Behavioral therapy may be offered,
especially for the therapy of accompanying sympto-
*See Special Opinion Chapter 5.7.5 and Repli-
in the guideline report chapter 4.3.
0
A
IIa-IV
Aids for Good Medicine www.degam-leitlinien.de71
Literature reference: [20,39],
https://www.awmf.org/leitlinien/detail/ll/051-001.html
https://www.nice.org.uk/guidance/ng206
For details see chapter 5.4, 5.7 and 6.1, 6.3.
Preliminary note
The overall view of the studies (see 4.2) shows that a clearly determinable and directly
treatable cause, especially of a somatic nature, is rare in cases of primary unexplained fatigue.
Rather, in addition to addressing the family and broader social context, symptom-oriented
symptom-oriented treatment is often indicated. This should depend on the type and extent of the symptoms,
the functional impairment, the associated feelings and perceptions.
To facilitate a conversation about this, a symptom diary can be helpful. To
guideline, counseling aids/patient information have been developed that support three
counseling issues: activating measures, overuse complaints/de-
tension procedures, and counseling about sleep hygiene.
6.2 Drug therapy
The internationally published evidence on different forms of therapy for fatigue irrespective of an underlying somatic or
of fatigue independent of an underlying somatic or mental illness relates predominantly to
to ME/CFS or CFS without PEM as a mandatory criterion. As these are small and hetero-
and heterogeneous groups of patients, some with extreme symptom severity, these results are
results can only be applied with great caution to other patients.
The antidepressant fluoxetine [461] did not have a positive effect on ME/CFS, only a possible depressive comorbidity was found.
depressive comorbidity seems to be positively influenced [453].
[453].
There are several other studies on drug therapy in ME/CFS. None of them has
convincing evidence of efficacy. Euromene [21] lists such therapy trials.
For fatigue in general - i.e., not limited to ME/CFS - drug inter-
ventions have predominantly disappointed, with substantial placebo effects observed
[462-464], or are methodologically inadequate/inconsistent [465]. Thus, a tes-
tosterone administration did not improve vitality at slightly lower levels [381], and melatonin also
melatonin did not cause a relevant change in daytime sleepiness [466], but may be effective in the case of
However, it may be helpful in cases of insomnia that are not sufficiently alleviated by behavioral measures [21].
The psychostimulants methylphenidate and modafinil are recommended in guidelines for the following disorders.
as a justifiable therapeutic attempt for fatigue that cannot be influenced in any other way.
listed: Parkinson's disease [467]
https://www.awmf.org/leitlinien/detail/ll/030-010.html,
multiple sclerosis [468]
https://www.awmf.org/leitlinien/detail/ll/030-050LG.html and tu-
morassociated fatigue [45]
https://www.leitlinienprogramm-onkologie.de/leitlinien/sup-
portive-therapy/. To date, there is no robust evidence-based basis for this; moreover, the use of these
the use of these substances for the three indications represents an off-label use with all the legal
legal consequences, which is why the guideline group does not support the use of these substances for the therapy of fatigue.
for the treatment of fatigue is critical. Pitolisant improves daytime sleepiness in OSA patients.
in OSA patients. This is countered by considerable side effects and unclear cardiovascular si-
safety, and the substance is currently not approved for this indication in Germany [469].
approved in Germany [469].
In a small short-term study, a phytopreparation (valerian, hops, jujube) improved pri-
mary insomnia improved sleep quality and daytime sleepiness [470]. Withdrawal of sleeping pills (benzodi-
azepines or Z-substances) improves daytime sleepiness- even in those who have not com- pletely discontinued
pletely discontinued, although tending to a lesser extent [471]. Avoidance of
alcohol and sedatives before bed improves symptoms of obstructive sleep apnea [19].
Sleep Apnea [19]
https://www.awmf.org/leitlinien/detail/ll/063-001.html.
There is evidence of improvement in quality of life, as well as fatigue and generalized
performance with i.v. iron supplementation in patients with heart failure and proven iron deficiency.
proven iron deficiency, even with normal Hb levels [472,473]. Oral iron substituti
iron deficiency without anemia in endurance athletes and menstruating women with fatigue.
menstruating women with fatigue [474-478]. In some cases
in some cases the blinding was insufficient [132,134,479]. From these studies it can be concluded that
in mild iron deficiency without anemia (ferritin < 50 μg/l), the substitution effects are probably
Placebo effects. However, when ferritin levels were below 15 μg/l or transferrin saturation < 20%
however, tired women of childbearing age (and thus regular mens-
trual blood loss) benefited from substitution in terms of fatigue and general performance.
ability.
It is unlikely that iron supplementation in otherwise healthy individuals and
without severe iron deficiency or anemia, because this is usually much more influenced by other factors.
influenced much more significantly by other factors. The benefit of a treatment
with a largely harmless oral therapy, which is not covered by the GKV if the patient is 12 years or older
years of age, the risk of fixation on an inadequate approach to the solution is
inadequate approach.
In pregnant women, the US Preventive Task Force does not recommend iron supplementation in the absence of anemia.
deficiency without anemia because the data only showed clear improvements in blood parameters.
improvements in blood parameters but no consistent positive effects on maternal or fetal health [480].
maternal or child health [480]. Iron overload, on the other hand, is potentially harmful
[481,482].
In cases of proven iron deficiency, substitution can be achieved with dietary changes
[595], iron-fortified foods [483], or oral substitution, especially
if the cause of the deficiency cannot be corrected in the long term. Regarding the form of iron substitution
in premenstrual women, there is a Cochrane review [484], according to which continuous
administration is somewhat more effective than intermittent oral supplementation. In the global recommendations
on iron supplementation in women of reproductive age should also include social aspects
[485].
Increasingly, parenteral substitution is being advocated, especially since a number of studies have exclusively used this form of therapy.
exclusively this form of therapy. Due to the approval status of these preparations and the
guidelines on drug therapy, the following restrictions apply, for example, to the prescription of
iron carboxymaltose (adapted from Ferinject):
Aids to Good Medicine www.degam-leitlinien.de75
n The laboratory-chemical blood test must prove an iron deficiency
n From the physician's point of view, oral iron preparations are unsuitable or ineffective for those affected.
Reasons for this may include poor tolerance of a previous oral iron therapy, difficulty in swallowing
therapy, swallowing difficulties or diseases that preclude adequate iron absorption (e.g., inflammatory
absorption (e.g. underlying inflammatory diseases, absorption disorders). A therapy
with an oral iron preparation does not necessarily have to precede the prescription of i.v. iron carboxymaltose.
i.v. does not necessarily have to precede the prescription. If the physician is considering oral therapy and concludes that
and comes to the conclusion that oral iron is ineffective or not applicable for other
reasons, iron carboxymaltose can also be used as initial therapy.
therapy.
n If the physician decides against oral iron therapy, he or she must be able to justify this medically.
medical justification - it is advisable to document the justification.
worthwhile. In this case, the prescription in drop form should also be considered,
because in the case of intolerance to tablets, the use of appropriate drops is often successful.
drops is often successful.
Because of the rare but potentially serious side effects of parenteral iron therapy, careful patient education is essential.
careful patient education and adherence to appropriate safety standards are particularly important.
and adherence to appropriate safety standards are particularly important.
