Chemistry Reference
In-Depth Information
Another early indication for lactulose therapy was the amelioration of hepatic
encephalopathy (PSE).
7-10
Although the precise cause of the progressive clouding of
sensorium with advancing liver functional deterioration is likely multifactorial, the
role played by ammonia produced in the gut is preeminent in pathogenesis, and meth-
ods to reduce its formation are the key to successful therapy.
29
Early reports compar-
ing nonabsorbable antibiotic with lactulose showed equivalence in low-grade PSE.
30
The benefit of this treatment in subclinical PSE, which can only be diagnosed with
psychometric tests, has now been shown.
31
Physiological studies where lactulose was
incubated
in vitro
with stool from healthy volunteers revealed that it inhibits short-
chain fatty acids produced from protein via a marked drop in pH,
32
reduced ammonia
concentrations, and increased nitrogen excretion.
22,33
In addition, acetate and lactic
acid with reduction of pH also trap nonlipid-soluble ammonia in the colon.
34
Lactulose has also been used to reduce the rate of
Salmonella
carriage in chronic
carriers and apparently this was also an early indication recognized in some coun-
tries.
7
Similarly, the carrier rate of
Shigella
was reported to be reduced.
35
However, a
rat model of the effects of lactulose on infection showed that while colonization was
reduced with
Salmonella,
translocation into the host was increased.
36
Currently, this
indication for lactulose is not used in North America.
Other clinical situations exist in which lactulose may potentially help. Oral lactu-
lose was given to patients in a nonrandomized controlled study in the pericholecys-
tectomy operative period and was found to reduce postoperative sepsis in patients
with obstructive jaundice.
37
Both a reduction in circulating endotoxin and tumor
necrosis factor-α (TNF-α), a key cytokine induced by endotoxin, has been shown
with lactulose in animal models.
38,39
These effects could be also attributed to the
bifidogenic impact of lactulose. In at least one model, contamination with galactose,
limiting hepatotoxicity of galactosamine, may have been more relevant.
40
However,
another
in vitro
study found that lactulose directly inhibits TNF-α.
41
The hypoth-
esis raised was that, in patients with biliary obstruction, intestinal permeability is
increased, which allows the disaccharide to be absorbed in larger amounts, leading
to TNF-α inhibition, which then attenuates endotoxin effects.
Lactulose is also postulated to affect several metabolic processes. First, it was
reported in a human study that after a week of treatment of dyslipidemic patients,
there was a 17 percent decrease in serum cholesterol lasting for at least 4 weeks
after discontinuation.
42
In a small-animal model, reduction of serum cholesterol and
the lithogenic index (a marker for gallstone formation risk) was found to be more
effective with a combination of lactulose and lignin, than with the latter substance
alone.
43
More recent studies on lipids conflict with these earlier reports. De Preter et
al.
25
did not find that long-term lactulose changed serum lipids in healthy volunteers.
In another human study, Vogt et al.
44
also failed to show an effect of 4 weeks of
lactulose on serum cholesterol in healthy men. They did find a 10 percent decrease
of serum triglycerides in this partial randomized cross-over trial.
44
Opposite effects
of lactulose were observed by Jenkins et al.,
45
again in healthy volunteers. After 2
weeks consumption of 18 to 25 g of lactulose, fasting total and low density lipopro-
tein associated serum cholesterol were higher by 9 percent.
45
The authors felt that
rapid fermentation of lactulose raised acetate levels contributing to lipid metabolism.
