Neurocritical Care (2018) 28:154–156
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NEUROCRITICAL CARE THROUGH HISTORY
Lactulose: A Simple Sugar in a Complex Encephalopathy
Eelco F. M. Wijdicks1
Published online: 2 January 2018
Ó Springer Science+Business Media, LLC, part of Springer Nature 2017
Abstract
Hepatic encephalopathy is a common encephalopathy and one of the very few that are treatable. Lactulose has remained a
standard pharmaceutical intervention and is listed as one of the World Health Organization’s Essential Medicines. The
discovery of lactulose, the acid dialysis proof of concept, and the role of Bircher are not well known. This historical
vignette reviews the gradual understanding of the complex liver–brain connection, the effective treatment of hepatic stupor
with lactulose, and the immediate relevance of lactulose to the practice of consultative neurocritical care.
Keywords Lactulose Hepatic encephalopathy Portal-systemic encephalopathy Ammonia Johannes Bircher
Introduction emphasizing the abnormal ammonia metabolism. The
‘‘flapping tremor’’ was again mentioned, described as ‘‘a
The neuropsychiatric manifestations of chronic (and acute) series of rapid flexion–extension movements at the
liver failure have been well known since time immemorial metacarpophalangeal and wrist joints, often accompanied
and, when severe, are accepted as a diagnostic sign of by lateral–lateral movement of the digits.’’ A few years
progressive disease. Contributions to the clinical presen- later, Parsons-Smith and colleagues described the charac-
tation came from both hepatologists and neurologists with teristics of the electroencephalogram (EEG), expanding on
little collaborative work. Hepatic encephalopathy and Foley’s early work. The most distinctive pattern was alpha
decreased consciousness had already been noted in von rhythm interrupted by medium voltage, 5–6 waves per
Frerichs’ classic work in 1860 [1]. The book linked the second, most commonly over the temporal and frontal
emergence of jaundice and marked the development of lobes—with remarkably few triphasic waves [4]. The
delirium, convulsions, and coma. However, better clinical EEGs showed good correlation with the grade of hepatic
understanding had to wait for contributions by Sherlock coma but poor correlation with serum or cerebrospinal fluid
and Adams and Foley to the description of hepatic (CSF) ammonia levels.
encephalopathy. A landmark paper by Adams and Foley First reports of cerebral edema in acute liver failure
[2] substantially delineated clinical symptoms and patho- emerged in the early 1970s along with better separation of
logical changes of the brain. This clinicopathological study fulminant hepatic failure (‘‘massive liver cell necrosis’’) as
introduced asterixis as a key finding and effectively dis- a clinical entity due to acute worsening chronic liver dis-
missed the misnomer ‘‘flapping tremor’’ (which was not a ease [5]. Neurologists were slow to accept cerebral edema
tremor but actually a movement caused by sudden loss of as a phenomenon in fulminant hepatic failure; it was con-
posture). A year later, many neurologic findings were sidered controversial. Some felt that the autopsies lacked
summarized in a key paper by Sherlock [3], who coined the detail. ‘‘None of the reports included descriptions of the
term portal-systemic encephalopathy. The paper discussed brain by experienced neuropathologists,’’ or the observa-
the presumed nature of hepatic encephalopathy tion was possibly considered ‘‘a terminal complication’’
[6]. One study using both dexamethasone and mannitol
decreased intracranial pressure in patients with mildly
& Eelco F. M. Wijdicks increased intracranial pressures [7].
[email protected] Hepatic encephalopathy in chronic liver disease is a
1
Division of Critical Care Neurology, Mayo Clinic, 200 First neurologic syndrome with variable clinical features. Poor
Street SW, Rochester, MN 55905, USA response to normal stimuli, aloofness, and dozing off are
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Neurocritical Care (2018) 28:154–156 155
characteristic of the earlier stages. Sherlock’s group found would diminish ammonia absorption, and some studies
that patients with neurologic signs had higher serum [10, 11] found reduction in ammonia correlated with
ammonia levels, often twice the upper limit of normal [8]. decreased stool pH. Earlier, Ingelfinger suggested a role for
Nitrogenous substances from the intestine would traffic to lactulose in encephalopathy after others found that lacto-
the systemic circulation by portal systemic collateral ves- bacilli used lactulose to form lactic acid, thereby creating a
sels occurring spontaneously or resulting from surgical situation promoting growth at the expense of other gut
portacaval shunts [3]. Oral administration of urea in bacteria [12, 13].
experimental studies and increased dietary protein resulted Two patients with chronic portal-systemic
in worsening encephalopathy similar to a gastrointestinal encephalopathy were sequentially treated with several
hemorrhage. Suppressing the bacterial flora with neomycin regimens, which changed weekly. The administered drugs
was standard but associated with diarrhea, staphylococcal were neomycin, sorbitol, and lactulose. In both patients,
enterocolitis, ototoxicity, and nephrotoxicity. There was lactulose dramatically reversed encephalopathy with dis-
therefore an incentive to search for another approach. appearance of flapping tremor but with risk of relapsing
coma if sorbitol was substituted for lactulose. The
encephalopathy was graded according to Parsons-Smith
The Lactulose Story criteria [4] and encephalopathy on EEG by Guggenheim
criteria [14]. The lactulose supplied by Philips-Duphar was
Johannes Bircher (Fig. 1), currently professor emeritus of known as duphalac (orange-flavored syrup ordinarily used
medicine and clinical pharmacology in Switzerland, pub- for the treatment of constipation). Ammonia levels dropped
lished his first experiment with lactulose in The Lancet in with improving encephalopathy and vice versa.
1966 [9]. Despite dramatic clinical response, this treatment
was met with skepticism. A leading hepatologist even
asked Dr. Bircher, ‘‘Do you think, Hannes, a simple sugar Discussion
like lactulose could do any good in such a complicated
disease?’’ (Bircher, personal communication). Acceptance Lactulose is a simple disaccharide made of fructose and
came after a randomized trial in 1969 [10] and endorse- galactose (Fig. 2). The working concept was that lactulose
ment by leading authorities in liver disease. is not absorbed in the small bowel but broken down to
Bircher’s idea was that lactulose is not absorbed in the lactic acid in the colon followed by a decrease in intestinal
small bowel and therefore reaches the colon. There it pH. The growth of lactobacilli reduces hyperammonemia
nourishes the colonic growth of lactobacilli, which produce because these bacteria cannot split urea into ammonia.
no urease and less ammonia. Acidification of the colon However, subsequent studies showed that lactobacilli grew
even after reduction in ammonia levels. Low pH may cause
an increase in NH4 ions, which are nonabsorbable. A
subsequent double-blind clinical trial of lactulose in seven
patients resulted in improvement of five patients and
proved that lactulose worked according to ‘‘the concept of
non-ionic diffusion.’’ In this trial, after administration of
lactulose, a patient with acquired hepatolenticular
Fig. 2 Chemical structure of lactulose—a disaccharide consisting of
Fig. 1 Johannes Bircher, used with permission fructose and galactose
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156 Neurocritical Care (2018) 28:154–156
degeneration showed marked improvement in cognitive 6. Plum F, Posner JB, editors. The diagnosis of stupor and coma. 3rd
domains and disappearance of choreoathetosis. ed. Philadelpha: F. A. Davis Co.; 1980.
7. Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams
The evidence for lactulose as a first treatment is largely R. Controlled trial of dexamethasone and mannitol for the cere-
based on clinical experience. A systemic review revealed bral oedema of fulminant hepatic failure. Gut. 1982;23:625–9.
that most studies were performed in the early 1970s and 8. Phear EA, Sherlock S, Summerskill WH. Blood-ammonium levels
were of low quality (by today’s standards) [10, 15–18]. in liver disease and hepatic coma. Lancet. 1955;268:836–40.
9. Bircher J, Muller J, Guggenheim P, Haemmerli UP. Treatment of
Lactulose did not improve mortality, and the effect was in chronic portal-systemic encephalopathy with lactulose. Lancet.
the long run not sustained. Many other pharmacologic 1966;1:890–2.
therapies (scavengers, polyethyleen glycol etc) are cur- 10. Elkington SG, Floch MH, Conn HO. Lactulose in the treatment of
rently being studied [19]. chronic portal-systemic encephalopathy. A double-blind clinical
trial. N Engl J Med. 1969;281:408–12.
One way or another, sugars play a major role in the 11. Haemmerli UP, Bircher J. Wrong idea, good results (the lactulose
treatment of liver disease. Lactulose in worsening story). N Engl J Med. 1969;281:441–2.
encephalopathy correlated with chronic liver disease, and, 12. Hoffmann K, Mossel DA, Korus W, Van De Kamer JH. Studies
as mentioned earlier, mannitol in brain edema often on the mechanism of action of lactulose (beta-galactoside action
of lactulose (beta-galactosido-fructose) in the intestine. Klin
appearing in the worst cases of with fulminant hepatic Wochenschr. 1964;42:126–30.
failure [18]. Antibiotics did not disappear, and neomycin 13. Ingelfinger FJ. Discussion of paper by Hoffmann, K., et al. (Klin.
was replaced by rifaximin, which is mostly used as a sec- Wchnschr. 42:126–130, 1964). In: Beeson PB, editor. Year Book
ond-line intervention. However, there is a sweetness of of Medicine 1964–1965. Chicago: Year Book Medical Publish-
ers; 1964–1965. pp. 591–592.
success in treatment of acute liver failure. 14. Guggenheim P, Regli F, Hafen G, Haemmerli UP. Electroen-
cephalographic studies in chronic liver disease before and after
Acknowledgements I thank Dr. Bircher for providing crucial morphine administration: attempt at an objectivation of the
information. diagnosis ‘‘Precoma’’ and ‘‘Hepatic Coma’’. Dtsch Med
Wochenschr. 1964;89:748–55.
15. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccha-
References rides for hepatic encephalopathy: systematic review of ran-
domised trials. BMJ. 2004;328:1046.
16. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol and
1. Frerichs FT. A clinical treatise on the diseases of the liver, vol. lactulose in the treatment of acute portal-systemic encephalopa-
I. New York: William Wood & Co.; 1879. thy. A controlled, double-blind clinical trial. Am J Dig Dis.
2. Adams RD, Foley JM. The neurological disorder associated with 1978;23:398–406.
liver disease. Res Publ Assoc Res Nerv Ment Dis. 17. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC,
1953;32:198–237. Seeff L, Levy LL. Comparison of lactulose and neomycin in the
3. Sherlock S, Summerskill WH, White LP, Phear EA. Portal-sys- treatment of chronic portal-systemic encephalopathy. A double
temic encephalopathy; neurological complications of liver dis- blind controlled trial. Gastroenterology. 1977;72:573–83.
ease. Lancet. 1954;267:454–7. 18. Simmons F, Goldstein H, Boyle JD. A controlled clinical trial of
4. Parsons-Smith BG, Summerskill WH, Dawson AM, Sherlock S. lactulose in hepatic encephalopathy. Gastroenterology.
The electroencephalograph in liver disease. Lancet. 1970;59:827–32.
1957;273:867–71. 19. Rahimi RS, Rockey DC. Hepatic encephalopathy: pharmaco-
5. Record CO, Chase RA, Hughes RD, Murray-Lyon IA, Williams logical therapies targeting ammonia. Semin Liver Dis.
R. Glycerol therapy for cerebral oedema complicating fulminant 2016;36:48–55.
hepatic failure. Br Med J. 1975;2:540.
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