[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture]. / Veränderung des 24-Stunden-Rhythmus von Plasma-Melatonin bei Patienten mit Leberzirrhose--Beziehung zur Schlafarchitektur.

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

Disruption of circadian locomotor activity in rats after portacaval anastomosis is not gender dependent.

A recent study suggested that female rats are less affected by a portacaval anastomosis (PCA) than their male counterparts, as measured by body weight and changes in locomotor activity. In this study, we evaluated the entrainment of locomotor activity to the light/dark (LD) cycle, a consistent abnormality in the portacaval shunted rat. The degree of entrainment was measured in male and female rats before and after PCA or sham operation. All four groups of animals showed strong entrainment to an LD cycle before surgery. After portacaval anastomosis, male and female rats exhibited a highly significant decrease in overall motor activity as compared with the preoperative period and as compared with sham-operated animals of the same gender. The percentage of total activity during daytime was significantly increased after portacaval anastomosis. The reduction in parameters of entrainment indicates a disruption of circadian function in both portacaval-shunted groups. Portal pressure measurements confirmed the patency of the shunts. Cortical brain glutamine levels were similarly increased in male and female shunted rats. The loss of body weight was slightly, but not significantly, more pronounced in male animals after shunt surgery. In conclusion, our results do not support a role for gender in the disruption of circadian function in rats after PCA.

A low-protein diet ameliorates disrupted diurnal locomotor activity in rats after portacaval anastomosis.

In previous studies we noted a disruption of the circadian locomotor activity rhythm in rats after portacaval anastomosis (PCA). To examine whether this abnormality is related to factors that aggravate hepatic encephalopathy in humans, we studied the effect of dietary formulation and protein content on body weight, locomotor activity, and entrainment to the light-dark cycle in rats after PCA or sham operation. Postoperative weight loss was prevented by pair-feeding with a purified liquid diet. However, the behavioral abnormalities persisted in PCA rats fed a high-protein diet, with a reduction in total activity and entrainment to the light-dark cycle. These were ameliorated by a low dietary protein content. Since this treatment reduces the load of gut-derived nitrogenous substances that might alter brain metabolism, our data strengthen the hypothesis that the abnormal circadian activity patterns in PCA rats may be part of the spectrum of hepatic encephalopathy.

Disruption of the diurnal rhythm of plasma melatonin in cirrhosis.

OBJECTIVES: To assess 24-hour plasma melatonin profile as a marker of output rhythm from the circadian clock and to study sleep diaries as reflections of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. SETTING: Clinical research center in a university hospital. PATIENTS: Seven patients with cirrhosis but not alcoholism and seven age-, sex-, and education-matched controls. MEASUREMENTS: Neuropsychological testing to confirm subclinical hepatic encephalopathy. Plasma melatonin levels measured every 30 minutes for 24 hours by radioimmunoassay. Sleep diaries kept for 1 week before admission. RESULTS: Patients with cirrhosis had markedly elevated melatonin levels during daytime hours; in addition, the time of onset of melatonin increase and the time at which melatonin levels peaked were consistently and significantly delayed in these patients. Sleep diaries indicated more nocturnal awakenings and more frequent daytime naps in patients with cirrhosis. CONCLUSION: Disruption of the diurnal rhythm of melatonin may reflect alterations of circadian function that could contribute to the disturbances of the sleep-wake cycle frequently seen in patients with cirrhosis.

The relation of iron status and hemochromatosis gene mutations in patients with chronic hepatitis C.

BACKGROUND & AIMS: Elevated hepatic iron concentration may affect the response to antiviral therapy in chronic hepatitis C. This study explored the contribution of genetic hemochromatosis to iron accumulation in chronic hepatitis C. METHODS: HFE mutations (C282Y and H63D) were assessed in 184 patients with chronic hepatitis C virus and 487 controls. Liver biopsy specimens were available in 149 patients. Hepatic iron content was measured in 114 patients by atom-absorption spectrophotometry. RESULTS: The C282Y and H63D allele frequencies were 7.06 and 11.6 in patients and 4.83 and 11.09 in controls, respectively. Eight patients were homozygotes (5 C282Y [2.7%] and 3 H63D [1.6%]), 2 compound heterozygotes (1%), and 49 heterozygotes (14 C282Y [7.6%] and 35 H63D [19%]). Biochemical evidence of iron overload was more common in patients with HFE mutations (28 of 47) than in those without (34 of 102; P = 0.0045). Histological iron grading and hepatic iron content overlapped among patients with or without mutations. A hepatic iron index of >1.9 was observed only in 1 of the 4 C282Y homozygotes and 1 of the 3 H63D homozygotes. CONCLUSIONS: HFE mutations contribute to but do not fully explain hepatic iron accumulation in chronic hepatitis C. Furthermore, C282Y or H63D homozygosity in chronic hepatitis C is not necessarily associated with a high hepatic iron content.