Relief from profound fatigue associated with chronic liver disease by long-term ondansetron therapy
E Anthony Jones
The Lancet; vol 354, Number 9176 31 July 1999

A woman with chronic hepatitis C and profound fatigue became symptom free when treated long-term with ondansetron 4 mg twice daily. Altered central serotoninergic neurotransmission may contribute to fatigue complicating chronic liver disease.

comment- These study results suggest HCV related fatigue may be treatable with other than antiviral therapy. And suggests a mechanism of action causing the fatigue.
Jules Levin

The mechanism of fatigue in patients with chronic liver disease is unknown, but altered central serotoninergic neurotransmission may contribute.1,2 If altered neurotransmission is involved, a serotonin-receptor-subtype antagonist might help.

In 1992, a 35-year-old woman sought advice for profound fatigue that impaired her ability to work. She also had mild generalised pruritus. Before she had any symptoms, she had had a blood transfusion. Her weight was 42·5 kg and the liver edge was palpable. Results of laboratory tests included the following: total bilirubin 8 µmol/L; alkaline phosphatase 51 U/L; gamma-glutamyl transpeptidase 58 U/L; alanine aminotransferase 41 U/L; HCV RNA positive by PCR. A liver biopsy specimen showed portal hepatitis. Antiviral therapy was not recommended. Her symptoms persisted. In 1996, a repeat liver biopsy specimen showed no change in the activity or stage of the disease, and she underwent a trial of treatment with the selective serotonin 5-hydroxytryptamine (HT)-type 3 receptor antagonist, ondansetron.

She was randomly assigned to receive, double-blind, one 8 mg tablet of ondansetron three times daily for 4 weeks and a placebo tablet three times daily for 4 weeks. During the first course, her symptoms were unchanged. 4 days after starting the second course, her pruritus had subsided, but she had become constipated. She reduced her dose to two tablets daily. 2 days later she developed fluctuating diplopia, which resolved after a few days. Despite dietary advice and laxatives, she was constipated for the remainder of the trial. Nevertheless, at the end of the trial, before breaking the treatment code, she was convinced that fatigue had been substantially less during the second course. Because constipation and diplopia are recognised side effects of ondansetron, the second course was predicted to be ondansetron, which was subsequently confirmed.

A severe exacerbation of her symptoms within 6 days of the end of the trial, induced the patient to request ondansetron. The side-effect of ondansetron-induced constipation was resolved by dose reduction, high roughage diet, and a high fluid intake. Between June, 1996, and April, 1997, she was treated with six courses of ondansetron, each lasting from several weeks to a few months. The drug was discontinued by the patient several times for reasons unrelated to its efficacy. Discontinuing it consistently precipitated sustained exacerbations of her symptoms; reintroducing it consistently induced sustained and complete ameliorations. She found that a dose of 4 mg twice daily was the optimum dose. On this dose, her energy level was normal and no intestinal or other adverse events occurred. 4 mg daily did not work. 4 mg three times a day induced constipation. A recurrence of symptoms would start within 24 h of stopping the drug. While taking ondansetron, she was able to work more efficiently and for longer hours.

These findings support the hypothesis that altered central serotoninergic neurotransmission contributes to the profound fatigue that commonly complicates chronic liver disease. A relation between the serotonin system in the brain and fatigue is supported by two independent studies.3,4 First, in rats fatigue during extended periods of exercise correlated directly with indices of central serotoninergic transmission.3 Second, the serotonin-reuptake inhibitor, paroxetine, significantly reduced the exercise endurance time of athletes.4 These findings are compatible with altered transmission in neural pathways, on which 5-HT receptors are located, contributing to fatigue of central origin, and support the concept that excessive fatigue associated with chronic liver disease may be of central origin.5

At the time of writing this report, the patient has been taking ondansetron 4 mg twice daily continuously for 4 months and she was without symptoms.


REFERENCES-
1 Jones EA. Fatigue associated with chronic liver disease: a riddle wrapped in a mystery inside an enigma. Hepatology 1995; 22: 1606-08.

2 Jones EA, Yurdaydin C. Is fatigue associated with cholestasis mediated by altered central neurotransmission? Hepatology 1997; 25: 492-94.

3 Bailey SP, Davis JM, Ahlborn EN. Neuroendocrine and substrate responses to altered brain 5-HT activity during prolonged exercise to fatigue. J Appl Physiol 1993; 74: 3006-12.

4 Wilson WM, Maughan RJ. Evidence for a possible role of 5-hydroxytryptamine in the genesis of fatigue in man: administration of paroxetine, a 5-HT re-uptake inhibitor, reduces the capacity to perform prolonged exercise. Exp Physiol 1992; 77: 921-24.

5 Jalan R, Gibson H, Lombard MG. Patients with PBC have central but no peripheral fatigue. Gut 1996; 39 (suppl): A30.