Sleep disorders linked to Melatonin Part 2
Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy
AIM: To analyze pituitary hormone and melatonin circadian rhythms, and to correlate hormonal alterations with clinical performance, hepatic disease severity and diagnostic tests used for the detection of hepatic encephalopathy in cirrhosis.
METHODS: Twenty-six patients with cirrhosis were enrolled in the study. Thirteen patients hospitalized for systemic diseases not affecting the liver were included as controls. Liver disease severity was assessed by the Child-Pugh score. All patients underwent detailed neurological assessment, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), assays of pituitary hormone, cortisol and melatonin, and complete blood chemistry evaluation.
RESULTS: Pituitary hormone and melatonin circadian patterns were altered in cirrhosis patients without clinical encephalopathy. Circadian hormone alterations were different in cirrhosis patients compared with controls. Although cortisol secretion was not altered in any patient with cirrhosis, the basal cortisol levels were low and correlated with EEG and brain MRI abnormalities. Melatonin was the only hormone associated with the severity of liver insufficiency.
CONCLUSION: Abnormal pituitary hormone and melatonin circadian patterns are present in cirrhosis before the development of hepatic encephalopathy. These abnormalities may be early indicators of impending hepatic encephalopathy. Factors affecting the human biologic clock at the early stages of liver insufficiency require further study.
Hepatic encephalopathy, a major complication of cirrhosis, is a clinical syndrome characterized by mental status changes in patients with severe hepatic insufficiency. By contrast, the term “Minimal Hepatic Encephalopathy”, also known as subclinical hepatic encephalopathy (SHE) describes disturbances of several biological functions, including sleep and activities of daily living, in the absence of clinical neurologic symptoms1–3. Hormonal disorders and circadian rhythm abnormalities are often associated with liver disease4, and the severity of these disorders is related to liver disease severity and duration. The role of melatonin is critical, as diurnal melatonin rhythm disruption may significantly contribute to circadian function alterations5.
The main goal of the present study was to evaluate the circadian hormone secretion profile in cirrhosis patients without hepatic encephalopathy. Specifically, the study was designed to analyze the circadian rhythm of pituitary hormone, serum cortisol and melatonin, and correlate the hormone levels and 24-h hormone secretion abnormalities with brain magnetic resonance imaging (MRI) and electroencephalogram (EEG), which are used for the diagnosis of encephalopathy. In addition, the study also assessed the correlation between circadian hormone rhythm and the severity of hepatic disease as measured by the Child-Pugh score.
Twenty-six patients with cirrhosis were enrolled in the study. In addition, 13 patients hospitalized for various chronic diseases without liver or central nervous system (CNS) involvement were included as controls. We chose not to have a healthy control group, because hormone patterns in healthy people have been described in detail. Inclusion criteria were: age 35-75 years, abstinence from alcohol for at least 6 mo, cirrhosis confirmed by liver biopsy, and regular follow-up in our Liver Outpatient Clinic. Exclusion criteria were signs or symptoms of encephalopathy, any CNS or endocrine disease, use of medications with CNS effects, and illegal substance abuse.
Mean age was 64.6 ± 9.5 years in cirrhosis patients and 67.8 ± 10.8 years in controls. There were no significant differences between men and women.
The presence of characteristic brain MRI and EEG disturbances, and hormone abnormalities in cirrhosis patients without hepatic encephalopathy is the main finding of the present study.
Hepatic encephalopathy is a syndrome characterized by abnormal mental status in patients with severe liver disease6–8. SHE is a milder condition associated with cirrhosis and/or porto-systemic shunts. The diagnosis of SHE is clinically relevant because it may precede the development of overt hepatic encephalopathy. Moreover, the psychomotor deficits in SHE may impair cognitive function and activities of daily living2,3. SHE diagnosis is based on psychometric tests, EEG and brain MRI. However, since there is no “gold standard” for diagnosing SHE1–3,9, the prevalence of this condition in cirrhosis has been reported variously as 30% to 84%, possibly due to different diagnostic criteria used in the various studies.
Cirrhosis patients without clinical encephalopathy often demonstrate high basal ganglia MRI T-1 signal intensity, likely due to manganese deposition in the brain10–12.
EEG is useful in the diagnosis of SHE, as slow (2-5 Hz) high-amplitude frontal lobe waves are characteristic of early hepatic encephalopathy. Although EEG abnormalities are not encephalopathy-specific, abnormal theta and delta wave activity correlates with disease severity 13.
Several biological rhythm abnormalities, including impaired arterial pressure diurnal variation, nocturnal portal pressure rise, melatonin secretion and sleep pattern alterations occur in cirrhosis. The various mechanisms proposed to explain these circadian abnormalities include the following: (a) effect of neurotoxins on the suprachiasmatic hypothalamic nucleus (SCN), which is the “human biologic clock”14,15, and (b) elevated morning melatonin levels due to impaired liver melatonin metabolism, causing a circadian clock phase-shift16,17.
Liver diseases are associated with several hormone disorders, including decreased serum levels of T3, cortisol, testosterone, FSH and insulin, and elevated prolactin concentrations18–22. In addition, a characteristic high daytime melatonin pattern5 has been described; this may contribute to the sleep-wake cycle disturbances and hormone disorders, as SCN is located in the hypothalamus, which regulates pituitary hormones5,23–26.
Melatonin may act as an internal circadian body rhythm “synchronizer”, and plasma melatonin profile may be a circadian pacemaker marker. Therefore, melatonin rhythm disruption observed in cirrhosis may reflect circadian alterations with significant clinical implications: high daytime melatonin levels can cause an endogenous clock phase-shift and may therefore partly explain the sleep disturbances observed in cirrhosis5,27–29.
Additional factors, unrelated to melatonin but involved in liver failure, such as false neurotransmitters, cerebral amines and cerebral arteriovenous shunts may also contribute to hormonal circadian abnormalities in the early stages of hepatic encephalopathy. Our findings suggest that diurnal melatonin abnormalities correlate with the severity of liver disease in cirrhosis and may be identifiable early, before the development of clinical hepatic encephalopathy.
Prolactin secretion follows a pulsatile pattern, with a characteristic nocturnal rise, but cirrhosis is associated with elevated 24-h prolactin levels and loss of circadian prolactin rhythm30–32. However, our cirrhosis patients had significant prolactin circadian rhythm disturbances without baseline elevation. The differences between our findings and previous studies30,31 may be explained by patient selection, as we excluded patients with clinical encephalopathy.
A diurnal TSH secretion pattern, with the highest concentrations in late evening and the first hours of nocturnal sleep is well documented in normal subjects. Circadian TSH level variations may be modulated, in part, by a dopaminergic mechanism, which plays a major role in TSH rhythmicity in liver disease33–35. In our study TSH circadian abnormality was identified in the absence of clinical encephalopathy.
Although impaired cortisol inactivation is well documented in cirrhosis, basal circadian cortisol secretion remains stable36,37. In the present study, patients with cirrhosis had low 24 h cortisol levels compared to controls.
Our data suggests that cirrhosis patients without encephalopathy have disrupted melatonin, TSH and prolactin circadian cycle, and suppressed 24-h cortisol levels, but the circadian cortisol rhythmicity is unaffected. More importantly, the melatonin abnormalities (lower night levels) are more pronounced in advanced liver failure (Child score > 5). As these findings were not seen in controls, the hormone abnormalities identified in cirrhosis could be specific for liver disease.
We did not find any correlation between melatonin, TSH or prolactin levels with the severity of brain MRI or EEG abnormalities, but the lack of association may be a type-II error due to the small number of patients. Cortisol levels correlated with brain MRI abnormalities, EEG abnormalities and severity of liver disease (Child score > 5). Melatonin and cortisol abnormalities correlated with severity of liver disease, while TSH and prolactin levels did not. As we could not find any similar findings in the literature, we believe these observations deserve further investigation.
Our cirrhotic patients with SHE had abnormal circadian pituitary hormone secretion and diurnal melatonin cycle. The abnormal hormonal pattern in SHE is different compared to patients with systemic diseases not affecting the liver and healthy individuals. The presence of these abnormalities in cirrhotics without clinical encephalopathy raises the possibility that these patterns may represent indicators of early hepatic encephalopathy.
We believe that originality is the main strength of our study, as there are no published reports on pituitary hormone abnormalities in relation to the severity of hepatic encephalopathy. The main limitations include the study design (observational, no randomization, no power analysis, small patient number), and the attempt to make inferences about circadian patterns from three measurements per day.
An additional (fourth) measurement if obtained the following morning could have provided additional insight into the time course of the observed hormone changes. Since the number of statistical comparisons largely exceeded the number of cases and groups, positive findings should be interpreted with caution, because of the possibility of type I error. The inclusion of a healthy control group would have improved the study, and should perhaps be considered in future studies on this subject.
In conclusion, circadian hormone disturbances occur early in cirrhosis and are associated with disease severity. These observations raise the interesting hypothesis that alterations in circadian hormone secretion may be an early sign of impending clinical encephalopathy. This hypothesis has significant clinical implications and therefore, we believe, deserves further investigation.
Hepatic encephalopathy is a neuropsychiatric disorder associated with clinical manifestations ranging from slightly altered mental status to coma. The severity of symptom depends on the severity of liver disease, and the presence of metabolic or infectious complications.
The term “Minimal Hepatic Encephalopathy” includes biological disturbances such as that of sleep and daily activities, in the absence of neurologic symptoms. Abnormalities of psychometric tests, electroencephalogram (EEG) and brain magnetic resonance imaging (MRI) may support the diagnosis of Minimal Hepatic Encephalopathy.
Hormonal disorders and circadian rhythm abnormalities are often associated with liver disease, and the severity of these disorders is related to the severity and duration of the liver disease. The role of melatonin, a marker of intrinsic circadian pacemaker is critical, since diurnal melatonin rhythm disruption may reflect circadian function alterations leading to disturbances in the daily activities.
Circadian pituitary hormone alterations, brain MRI and EEG abnormalities have been described in cirrhosis. However, there is limited data on the relationship of these abnormalities with the severity of cirrhosis and hepatic encephalopathy. This field deserves further study.
Innovations and breakthroughs
This present study is the first attempt to evaluate circadian hormone abnormalities in relation to EEG, brain MRI, subclinical hepatic encephalopathy (SHE) and the severity of cirrhosis. The main finding is the presence of characteristic brain MRI, EEG and hormone secretion abnormalities in cirrhosis patients with SHE.
Our data suggests that melatonin and pituitary hormone circadian rhythm abnormalities are present early in the course of cirrhosis and are associated with the severity of liver disease in patients without clinical encephalopathy. These findings raise the interesting hypothesis that circadian hormone abnormalities may be an early sign of the development of hepatic encephalopathy.
Circadian rhythm means a predictable physiologic fluctuation in a 24 h period; SHE is a clinical entity consisting of mild neuropsychological abnormalities affecting the activities of daily living in cirrhosis patients without clinical encephalopathy.
This is a non-randomized observational study with novel and interesting findings, demonstrating that abnormal pituitary hormone and melatonin circadian patterns are present in cirrhosis patients without hepatic encephalopathy. The manuscript is well written.