Chronobiology: Clockwork Organs

5. October 2015

Chronoprevention and chronotherapy are old topics, ones to which modern medicine is currently returning with a fresh mindset. One research team has now systematically listed previous findings on circadian rhythms of organs and diseases.

The reasons for the different time sequences are diverse. For one thing, scientists think in terms of a genetically defined clock which controls the operations in the organ systems. There are in addition also internal factors such as neuroendocrine-based, hormonal, immunological and sympathetic /parasympathetic influences that are closely linked to both the body clock as well as to external influences such as, for instance, chiaroscuro rhythms, seasons, one’s own activities, sleep-wake rhythm, eating habits, medications.

Scientist Michael H. Smolensky and colleagues from the University of Texas (USA), the University of Ferrara (Italy), the University of Vigo (Spain) and the University of Minnesota (USA) have put together two detailed reviews [Paywall] on circadian rhythms of human organisms and different diseases.

Rhythms in the head

While migraine headaches typically develop in the morning between 4 and 9 o’clock both in adults and in children, cluster headache occurs frequently during the REM sleep at between 0 and 3 am. Tension headaches, however, are the result of prolonged stress during the day and are therefore usually a problem in the late afternoon. They appear very rarely in the early morning. Cyclic vertigo, possibly an expression of vestibular migraine, torments sufferers mostly in the morning.

“Red eye” (conjunctival hyperemia), a sign of conjunctivitis, usually worsens upon wakening in the morning. At noon, the pains recede significantly, while they worsen in the evening once again up until bedtime. This cycle corresponds to the natural circulation and temperature fluctuations of the conjunctiva. Keratoconjunctivitis sicca (dry eye), however, worsens steadily during the day and torments those affected most strongly at night.

Daily fluctuations in heart and circulation

A time point between 6 a.m. and 12 midday is when sudden cardiac death is found to occur most frequently. Patients with ST-segment elevation myocardial infarction turn up in the emergency room mostly at night. Supraventricular and ventricular arrhythmias occur mostly during daytime activities. Sudden cardiac death of Type 1 diabetics, in bed sudden death syndrome (IBSDS), however, occurs almost exclusively during sleep. Many factors probably come into play here, such as QT interval prolongation, cardiac autonomic neuropathy as well as ventricular tachyarrhythmia accompanying acute hypoglycemia, according to the authors.

Symptoms of chronic heart failure such as oedema and difficulty in breathing are worse during the day and develop into medical emergencies especially at night. Acute myocardial infarction often occurs in the morning. People suffer heart attack in the late afternoon or early in the evening more rarely. The occurrence of myocardial infarction is most unlikely during the night. The situation is different under medication: in some studies there is evidence that patients treated with beta-blockers or ASS suffer heart attacks more rarely in the morning.

Blood pressure is subject to daily variation as well. Both systolic and diastolic measures rise rapidly in healthy people in the morning upon waking up and reach their peak during the day’s activities. In the late evening levels fall once again. During sleep, blood pressure is about 10-20% lower than it is during the day.

Both ischemic as well as haemorrhagic strokes are particularly common in the morning. Late afternoon or early evening is also when strokes quite often occur, whereas at night they are relatively rare. This pattern is to be found among normotensive as well as hypertensive people alike.

Deep vein thrombosis and pulmonary embolism occur between 10.30 and 12.30. Pulmonary embolism-related death also occurs most frequently in the morning, both among patients in the hospital as well as outside of it.

The respiratory system

Rhinorrhea is a particularly troublesome symptom as part of colds. The symptoms are worse in the evenings and also felt to be particularly bad late in the morning by most of those affected. Coughing by contrast is particularly strong at noon. Allergic symptoms worsen towards the evening as well. Many allergy sufferers cannot sleep at night because of symptoms. Allergic symptoms also manifest particularly sharply in the morning after waking up.

Asthmatic symptoms are repeatedly triggered during the day through foods and fragrances. Yet severe asthmatic symptoms manifest themselves mostly at night, especially at 4-5 am. This corresponds to the observation made as part of Chinese medicine: according to the Chinese organ clock the period from 3 to 5 o’clock in the morning is the “time of the lungs”. Patients with chronic obstructive pulmonary disease (COPD) require intubation treatment about three times more frequently between 0:00 and 8:00 than at other times.

Typical time of day for gastrointestinal disorders

In the stomach, acidity is particularly dominant in the late evening and early morning: pH is particularly low at these times. Oesophageal reflux, or a sour taste in the mouth, and sternum pains tear many sufferers from their sleep. Nevertheless variations exist: gastroesophageal reflux (GERD) plagues the “day-type” most during the day and the “night-type” most at night. Difficulties due to stomach ulcer are particularly acute in the period from late evening to early morning. The perforation of stomach ulcers, according to a study of 2,856 cases, in contrast most frequently occurs between 16 and 17 o’clock. Further typical times of day for gastrointestinal ailments:

  • Biliary colic usually occurs in the late evening or early morning.
  • Oesophageal variceal bleeding has its peaks in the period from 8:00 to 10:00 and 20:00 to 22:00.
  • Proctalgia fugax was already described 2,000 years ago by the Romans. The benign convulsions of Musculus pubococcygeus or levatorani occur almost exclusively at night, persisting for 20-30 minutes.

At night in the kidney

Most urine is excreted during the day, especially late in the afternoon or in the early evening hours. At night neurohypophysis releases relatively large amounts of vasopressin (ADH), so that the kidneys produce less urine at night. From the age of 40-45 years the distinct nocturnal ADH peak flattens, so more and more urine is also produced and secreted at night. Renal colic occur mostly at night – around the middle to late sleep stages.

Pain in the 24-hour cycle

Various pains are also subject to a 24-hour rhythm. Tooth pain due to caries occur most frequently at three to seven o’clock in the morning. Lower back pain and sciatica have a greater peak in the late evening and a smaller peak in the morning. Fibromyalgia pains are particularly frequent in the morning. Temporo-mandibular pain is worse during the day. Carpal-tunnel pains are often a problem at night. With pregnant women, labour mostly sets in between 0 and 4 clock in the morning.

Infections and fever

Acute fever with temperatures > 37° C accompanying bacterial infection sets in with high probability at 6-10 am. With viral infections, fever usually begins 16:00 to 22:00. In one study of meningococcal-meningitis involving 211 individuals, most patients presented in the clinic with severe symptoms in the afternoon. Death in cases of meningococcal meningitis occurred to half of such patients in the morning between 7 and 11 o’clock.

Cortisol-dependent Inflammatory diseases

Inflammatory diseases which are dependent on the circadian cortisol rhythm, such as allergies, infectious rhinitis, neurodermatitis, asthma and urticaria, then worsen when the body’s cortisol levels are low. Since the cortisol effect always enters with somewhat of a delay, the correlation observations which arise here involve slight time differences. Patients’ sleep is frequently interrupted by inflammation-related symptoms, so that those affected are especially unfocused and tired during the day.

Inflammatory skin diseases such as eczema, urticaria and neurodermatitis disturb patients mostly at night. Itching is particularly strong in the evening as well. Psoriasis occurs or is exacerbated mostly in the evening. Here as well, patients are regularly awakened due to experiencing severe itching, or once they are awake they experience strong itching.

Time for joint problems

With rheumatoid arthritis too the symptoms are more marked at those points in time during which cortisol concentrations in the blood are relatively low, and those affected are often afflicted at two to four o’clock in the morning. By contrast, patients with osteoarthritis suffer especially in the evening, after the joints have been loaded during the day. Gout was already described by the English physician Thomas Sydenham (1624-1698) and other well-known physicians in the 17th and 18th centuries with precision. The sharp pains and redness on the big toe, ankle, knee, wrist or elbow are often extremely strong at night.

Particularities with children

About 2% of children suffer from cyclic vomiting. It is characterised by nausea and vomiting that lasts about 6-48 hours, then completely disappears and reappears after a few weeks or months. Vomiting almost always starts at 4 to 8 o’clock in the morning. SIDS (sudden infant death syndrome) occurs very frequently at 6-12 o’clock, with a peak at 8 to 9 o’clock. Febrile seizures in children occur five times more often in the evening than in the morning.

The psyche during the course of the day

Depressions are often characterised by typical morning mood dips and by early morning awakening. With bipolar disorder the change from depression to mania takes place during the day. Suicide attempts are usually carried out during the period from early afternoon to early evening, while completed suicides occur very often during the period from late morning until early afternoon.

Understanding diseases better

Precise knowledge of the circadian rhythms of organs and diseases can help in detecting diseases more quickly, and in being better able to assess risks and use drugs in a more targeted manner. Chrono risk, chrono prevention and chronotherapy are old topics, ones to which current medicine are returning with a fresh mindset, and which can be combined beautifully with modern medicine. A healthy sleep-wake cycle helps in efforts to maintain health. The International Dark Sky Association (IDA), for example, is engaging itself to ensure that in our environs there is once again darkness at night, thereby enabling people to return to a healthier rhythm.

Original publications:

Diurnal and twenty-four hour patterning of human diseases: Cardiac, vascular, and respiratory diseases, conditions, and syndromes [Paywall]
Michael H. Smolenskya et al.; Sleep Medicine Reviews, doi.10.1016/j.smrv.2014.07.001; 2015

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions [Paywall]
Michael H. Smolenskya et al.; Sleep Medicine Reviews, doi: 10.1016/j.smrv.2014.06.005; 2015

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