663
proteins together with immunochemical analyses show only a quantitative reduction in adults and children with hypolactasia.6,7 Studies with cultured mucosa show that biosynthesis of LPH is decreased in patients with reduced enzymatic activity.8 Use of molecular probes by Sebastio et al9 to investigate developmental regulation of LPH in the intestine has led to surprising findings: in rabbits and rats there is a high concentration of LPH mRNA in enterocytes during the perinatal period. The concentration decreases as expected at weaning but
EDITORIALS
Lactose intolerance Human milk tastes sweet. It contains about 200 mmol/litre of lactose, a disaccharide also found in processed and ready-to-eat foods. Yet the capacity of an infant’s intestine to digest lactose is retained into adult life by only a minority of individuals, mostly those of northern European descent and certain other groups with a tradition of dairy farming. Lactose cannot be absorbed directly by the human gut: ingested lactose must be digested to glucose and galactose by a specific hydrolase in the intestinal mucosa.2 Maldigestion of osmotically active lactose in the gut lumen leads to retention of salt and water. The unabsorbed carbohydrate is fermented to short-chain organic acids and hydrogen by luminal bacteria. Thus, in an individual with lactase deficiency, ingestion of the sugar provokes pain due to distension of the bowel with fluid and gas, accompanied by borborygmi and diarrhoea. Since most of the adult population have a genetically determined deficiency of lactase-from 5% in northern European populations to more than 90% in Africa and Asia-and since lactose is ubiquitous, lactase deficiency is a common cause of abdominal distress. What is the basis for the decline of mucosal lactase activity after weaning in man and other mammals? Digestion of lactose is dependent upon lactasephlorizin hydrolase, a microvillar protein with p-D-
and galactosidase glycosyl-N-acylsphingosine activities.3 This enzyme is formed glucohydrolase after complex glycosylation of a high-molecularweight single-chain precursor4 but its exact mode of synthesis is unknown. The aminoacid sequence of human and rabbit lactase-phlorizin hydrolase (LPH)
has been deduced from cDNA clones.s There is
a
short signal sequence and a large "pro" portion of 849 aminoacids, neither of which appears in the mature membrane-bound enzyme; a membrane-spanning hydrophobic segment near the carboxy terminus that serves as an anchor; and a short hydrophilic cytosolic segment. Electrophoretic studies of microvillar
the mRNA reappears in adult animals. In human beings there is abundant lactase mRNA in individuals in whom lactase does not persist and steady-state mRNA concentrations do not correlate with enzyme activity.9 Organ culture and electron microscopic examination of human jejunal mucosa confirm that hypolactasia is associated with reduced quantities of LPH in the brush border and accumulation of nascent enzyme in the Golgi region.Similar studies have shown immunoreactive intracellular LPH precursor during the period of decline of lactase expression in developing mammals. The initial decline of lactase activity during development is compatible with transcriptional control of lactase expression, possibly associated with a shortened lifespan of the enterocyte.11 However, transcriptional control cannot account for the second phase of lactase decline. One suggestion is that the "pro" portion has a regulatory role in the post-translational processing of the prepro-LPH molecule. 5,9 The selective pressures that maintain the physiological decline of intestinal lactase activity in most adults are unknown; reduced risk of renal stones due to high calcium and vitamin D intake has been suggested. Lactose malabsorption can be suspected clinically from the relation between diet and symptoms and can be confirmed by the hydrogenlactose breath test.12 Breath hydrogen excretion determined by rebreathing two hours after an oral challenge with lactose reliably identifies individuals with lactase deficiency diagnosed by mucosal enzyme
assay.l3 What of treatment? Dietary exclusion of lactose is the best way to prevent symptoms in lactoseintolerant individuals. Complete elimination is not usually required since lactase deficiency is seldom absolute; nonetheless, there are many potential sources of lactose that should be sought when symptoms persist. An early strategy for preventing symptoms in lactose malabsorbers was the addition of 0-galactosidases purified from microorganisms; the disadvantage was that they had to be added to milk before ingestion and often changed the taste. 0-galactosidase has been commercially produced from the yeast Kluyveromyces lactis-’LactAid’. A rigorous trial in subjects with incomplete
carbohydrate absorption, as determined by challenge with milk, showed that 1 g of this preparation reduced breath hydrogen and symptoms.14 In children with
664
intolerance
lactose
but
without tablet
underlying
of gastrointestinal disease, has 0-galactosidase derived from Aspergillus oryzae proved effective.15 These studies show the feasibility of enzyme replacement therapy. Whether the cost of this treatment compared with simple dietary exclusion will permit its general use is unclear, but in view of the frequency of symptoms, many practitioners will be tempted to try it. a
form
FJ. Primary adult lactose intolerance and the milking habit: a problem in biological and cultural interrelations. Am J Dig Dis 1970; 15:
1. Simoons
695-70.
Dahlqvist A, Borgström B. Digestion and absorption of disaccharides in man. Biochem J 1961; 81: 411-18. 3. Skovbjerg H, Sjöström H, Norén O. Purification and characterisation of amphiphilic lactase-phlorizin hydrolase from human small intestine. Eur J Biochem 1981; 114: 653-61. 4. Danielsen EM, Skovbjerg H, Norén O, Sjöstrom H. Biosynthesis of intestinal microvillar proteins. Intracellular processing of lactasephlorizin hydrolase. Biochem Biophys Res Commun 1984; 122: 82-90. 5. Mantei N, Villa M, Enzler T, et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J 1988; 7: 2.
2705-13. 6.
Freiburghaus AU, Schmitz J, Schindler M, et al. Protein patterns of brush disorder fragments in congenital lactose malabsorption and in specific hypolactasia of the adult. N Engl J Med 1976; 294: 1030-32. 7. Skovbjerg H, Gudman-Hoyer E, Fenger HJ. Immunoelectrophoretic studies on human small intestinal brush border proteins-amount of lactase in adult-type hypolactasia. Gut 1980; 21: 360-64. 8. Sterchi EE, Lentze MJ, Naim HY. Molecular aspects of disaccharide deficiencies. Baillière’s Clin Gastroenterol 1990; 4: 79-96. 9. Sebastio G, Villa M, Sartorio R, et al. Control of lactase in human adult-type hypolactasia and in weanling rabbits and rats. Am J Hum Genet 1989; 45: 489-97. 10. Nsi-Emvo J, Launay F, Raul F. Is adult-type hypolactasia in the intestine of mammals related to changes in the intracellular processing of lactose? Cell Mol Biol 1987; 33: 335-44. 11. Smith MV, James PS. Cellular origin of lactase decline in postweaned rats. Biochim Biophys Acta 1987; 707: 89-97. 12. King CE, Toskes PP. The use of breath tests in the study of malabsorption. Clin Gastroenterol 1983; 12: 591-610. 13. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl
J Med 1975; 293: 1232-35. 14. Rosado JL, Solomons NW, Lisker R, et al. Enzyme replacement therapy for primary adult lactase deficiency. Gastroenterology 1984; 87: 1072-82. 15. Medow MS, Thek KD, Newman LJ, et al. &bgr;-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990; 144: 1261-64.
Cochlear implants prove their worth There have been several important developments since
the
editoriah on cochlear consists of one or more implant implantation. electrodes in or adjacent to the cochlea; a receiverstimulator, usually in the mastoid process of the temporal bone; and an external speech processor. The trend away from single-channel devices towards multichannel implants has continued. The most commonly used prosthesis is the 22-channel ‘Nucleus’ (Cochlear Corporation), which uses digital signals. Another popular device is ’Ineraid’ (Richards Medical), a 6-channel implant which uses analogue signals. A comparative study of patients with these two types of implant carried out at the University of Iowa2 showed that the devices performed equally well when listening conditions were quiet but Ineraid was 1988
An
Lancet
better in background noise. The speech-processing strategy used for Nucleus was subsequently altered to overcome this deficiency. Research continues on new speech processing strategies; Wilson et al3 lately reported improved speech recognition with continuous interleaved sampling, in which the different electrodes are stimulated separately rather than simultaneously. What about complications? Cohen et al4 conducted a survey of one hundred and fifty-two American surgeons who were using the Nucleus implant. There were 55 reported complications associated with 459 operations, the overall complication rate being 11 8%. There were no deaths but meningitis developed in 1 patient. The 23 major complications included perilymph fistula (3), electrical problems (9), and severe facial nerve stimulation (1). The researchers felt that most of the complications were avoidable and recommended that would-be implant surgeons should attend training courses and practise the technique in a temporal bone laboratory before operating on patients. Webb and colleaguess reported the complications associated with the first 153 operations carried out in Hannover, Germany, and the first 100 in Melbourne, Australia; the Nucleus device was regularly used in both centres. Wound breakdown requiring removal of the implant occurred in 0-6% of cases in Hannover and 1% of cases in Melbourne. Other complications included wound infection, electrode tie erosion via the external auditory meatus, electrode slippage, persistent increase in tinnitus, and facial nerve stimulation. There were no cases of meningitis in either series. Webb et al emphasise the importance of care in the design and management of the skin flap raised at the time of surgery. Partial ossification of the cochlea was thought to be a relative contraindication to implantation. However, Balkany et al6have reported successful implants in 15 profoundly deaf patients with ossification of the basal turn of the cochlea. Some degree of speech discrimination subsequently developed in 9. Cochlear implantation for children remains controversial. Although one might think that children with prelingual profound deafness have most to gain from implantation, these patients are the most difficult to rehabilitate postoperatively because they have no previous experience of sound. In children with normal hearing speech develops during the first 5 years of life;7 it seems that after the age of 7 the central nervous system is no longer able readily to acquire speech perception. Experience with implants in prelingually deaf individuals lends support to this view, but it must be borne in mind that an implant does not give normal hearing and that the degree of acquisition of speech discrimination varies from patient to patient. Theoretically, however, the ideal time for implantation in childhood would be during the first 3 years of life. The drawbacks are the difficulty in establishing that a child of that age is deaf enough to be
proteins together with immunochemical analyses show only a quantitative reduction in adults and children with hypolactasia.6,7 Studies with cultured mucosa show that biosynthesis of LPH is decreased in patients with reduced enzymatic activity.8 Use of molecular probes by Sebastio et al9 to investigate developmental regulation of LPH in the intestine has led to surprising findings: in rabbits and rats there is a high concentration of LPH mRNA in enterocytes during the perinatal period. The concentration decreases as expected at weaning but
EDITORIALS
Lactose intolerance Human milk tastes sweet. It contains about 200 mmol/litre of lactose, a disaccharide also found in processed and ready-to-eat foods. Yet the capacity of an infant’s intestine to digest lactose is retained into adult life by only a minority of individuals, mostly those of northern European descent and certain other groups with a tradition of dairy farming. Lactose cannot be absorbed directly by the human gut: ingested lactose must be digested to glucose and galactose by a specific hydrolase in the intestinal mucosa.2 Maldigestion of osmotically active lactose in the gut lumen leads to retention of salt and water. The unabsorbed carbohydrate is fermented to short-chain organic acids and hydrogen by luminal bacteria. Thus, in an individual with lactase deficiency, ingestion of the sugar provokes pain due to distension of the bowel with fluid and gas, accompanied by borborygmi and diarrhoea. Since most of the adult population have a genetically determined deficiency of lactase-from 5% in northern European populations to more than 90% in Africa and Asia-and since lactose is ubiquitous, lactase deficiency is a common cause of abdominal distress. What is the basis for the decline of mucosal lactase activity after weaning in man and other mammals? Digestion of lactose is dependent upon lactasephlorizin hydrolase, a microvillar protein with p-D-
and galactosidase glycosyl-N-acylsphingosine activities.3 This enzyme is formed glucohydrolase after complex glycosylation of a high-molecularweight single-chain precursor4 but its exact mode of synthesis is unknown. The aminoacid sequence of human and rabbit lactase-phlorizin hydrolase (LPH)
has been deduced from cDNA clones.s There is
a
short signal sequence and a large "pro" portion of 849 aminoacids, neither of which appears in the mature membrane-bound enzyme; a membrane-spanning hydrophobic segment near the carboxy terminus that serves as an anchor; and a short hydrophilic cytosolic segment. Electrophoretic studies of microvillar
the mRNA reappears in adult animals. In human beings there is abundant lactase mRNA in individuals in whom lactase does not persist and steady-state mRNA concentrations do not correlate with enzyme activity.9 Organ culture and electron microscopic examination of human jejunal mucosa confirm that hypolactasia is associated with reduced quantities of LPH in the brush border and accumulation of nascent enzyme in the Golgi region.Similar studies have shown immunoreactive intracellular LPH precursor during the period of decline of lactase expression in developing mammals. The initial decline of lactase activity during development is compatible with transcriptional control of lactase expression, possibly associated with a shortened lifespan of the enterocyte.11 However, transcriptional control cannot account for the second phase of lactase decline. One suggestion is that the "pro" portion has a regulatory role in the post-translational processing of the prepro-LPH molecule. 5,9 The selective pressures that maintain the physiological decline of intestinal lactase activity in most adults are unknown; reduced risk of renal stones due to high calcium and vitamin D intake has been suggested. Lactose malabsorption can be suspected clinically from the relation between diet and symptoms and can be confirmed by the hydrogenlactose breath test.12 Breath hydrogen excretion determined by rebreathing two hours after an oral challenge with lactose reliably identifies individuals with lactase deficiency diagnosed by mucosal enzyme
assay.l3 What of treatment? Dietary exclusion of lactose is the best way to prevent symptoms in lactoseintolerant individuals. Complete elimination is not usually required since lactase deficiency is seldom absolute; nonetheless, there are many potential sources of lactose that should be sought when symptoms persist. An early strategy for preventing symptoms in lactose malabsorbers was the addition of 0-galactosidases purified from microorganisms; the disadvantage was that they had to be added to milk before ingestion and often changed the taste. 0-galactosidase has been commercially produced from the yeast Kluyveromyces lactis-’LactAid’. A rigorous trial in subjects with incomplete
carbohydrate absorption, as determined by challenge with milk, showed that 1 g of this preparation reduced breath hydrogen and symptoms.14 In children with
664
intolerance
lactose
but
without tablet
underlying
of gastrointestinal disease, has 0-galactosidase derived from Aspergillus oryzae proved effective.15 These studies show the feasibility of enzyme replacement therapy. Whether the cost of this treatment compared with simple dietary exclusion will permit its general use is unclear, but in view of the frequency of symptoms, many practitioners will be tempted to try it. a
form
FJ. Primary adult lactose intolerance and the milking habit: a problem in biological and cultural interrelations. Am J Dig Dis 1970; 15:
1. Simoons
695-70.
Dahlqvist A, Borgström B. Digestion and absorption of disaccharides in man. Biochem J 1961; 81: 411-18. 3. Skovbjerg H, Sjöström H, Norén O. Purification and characterisation of amphiphilic lactase-phlorizin hydrolase from human small intestine. Eur J Biochem 1981; 114: 653-61. 4. Danielsen EM, Skovbjerg H, Norén O, Sjöstrom H. Biosynthesis of intestinal microvillar proteins. Intracellular processing of lactasephlorizin hydrolase. Biochem Biophys Res Commun 1984; 122: 82-90. 5. Mantei N, Villa M, Enzler T, et al. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J 1988; 7: 2.
2705-13. 6.
Freiburghaus AU, Schmitz J, Schindler M, et al. Protein patterns of brush disorder fragments in congenital lactose malabsorption and in specific hypolactasia of the adult. N Engl J Med 1976; 294: 1030-32. 7. Skovbjerg H, Gudman-Hoyer E, Fenger HJ. Immunoelectrophoretic studies on human small intestinal brush border proteins-amount of lactase in adult-type hypolactasia. Gut 1980; 21: 360-64. 8. Sterchi EE, Lentze MJ, Naim HY. Molecular aspects of disaccharide deficiencies. Baillière’s Clin Gastroenterol 1990; 4: 79-96. 9. Sebastio G, Villa M, Sartorio R, et al. Control of lactase in human adult-type hypolactasia and in weanling rabbits and rats. Am J Hum Genet 1989; 45: 489-97. 10. Nsi-Emvo J, Launay F, Raul F. Is adult-type hypolactasia in the intestine of mammals related to changes in the intracellular processing of lactose? Cell Mol Biol 1987; 33: 335-44. 11. Smith MV, James PS. Cellular origin of lactase decline in postweaned rats. Biochim Biophys Acta 1987; 707: 89-97. 12. King CE, Toskes PP. The use of breath tests in the study of malabsorption. Clin Gastroenterol 1983; 12: 591-610. 13. Newcomer AD, McGill DB, Thomas PJ, Hofmann AF. Prospective comparison of indirect methods for detecting lactase deficiency. N Engl
J Med 1975; 293: 1232-35. 14. Rosado JL, Solomons NW, Lisker R, et al. Enzyme replacement therapy for primary adult lactase deficiency. Gastroenterology 1984; 87: 1072-82. 15. Medow MS, Thek KD, Newman LJ, et al. &bgr;-galactosidase tablets in the treatment of lactose intolerance in pediatrics. Am J Dis Child 1990; 144: 1261-64.
Cochlear implants prove their worth There have been several important developments since
the
editoriah on cochlear consists of one or more implant implantation. electrodes in or adjacent to the cochlea; a receiverstimulator, usually in the mastoid process of the temporal bone; and an external speech processor. The trend away from single-channel devices towards multichannel implants has continued. The most commonly used prosthesis is the 22-channel ‘Nucleus’ (Cochlear Corporation), which uses digital signals. Another popular device is ’Ineraid’ (Richards Medical), a 6-channel implant which uses analogue signals. A comparative study of patients with these two types of implant carried out at the University of Iowa2 showed that the devices performed equally well when listening conditions were quiet but Ineraid was 1988
An
Lancet
better in background noise. The speech-processing strategy used for Nucleus was subsequently altered to overcome this deficiency. Research continues on new speech processing strategies; Wilson et al3 lately reported improved speech recognition with continuous interleaved sampling, in which the different electrodes are stimulated separately rather than simultaneously. What about complications? Cohen et al4 conducted a survey of one hundred and fifty-two American surgeons who were using the Nucleus implant. There were 55 reported complications associated with 459 operations, the overall complication rate being 11 8%. There were no deaths but meningitis developed in 1 patient. The 23 major complications included perilymph fistula (3), electrical problems (9), and severe facial nerve stimulation (1). The researchers felt that most of the complications were avoidable and recommended that would-be implant surgeons should attend training courses and practise the technique in a temporal bone laboratory before operating on patients. Webb and colleaguess reported the complications associated with the first 153 operations carried out in Hannover, Germany, and the first 100 in Melbourne, Australia; the Nucleus device was regularly used in both centres. Wound breakdown requiring removal of the implant occurred in 0-6% of cases in Hannover and 1% of cases in Melbourne. Other complications included wound infection, electrode tie erosion via the external auditory meatus, electrode slippage, persistent increase in tinnitus, and facial nerve stimulation. There were no cases of meningitis in either series. Webb et al emphasise the importance of care in the design and management of the skin flap raised at the time of surgery. Partial ossification of the cochlea was thought to be a relative contraindication to implantation. However, Balkany et al6have reported successful implants in 15 profoundly deaf patients with ossification of the basal turn of the cochlea. Some degree of speech discrimination subsequently developed in 9. Cochlear implantation for children remains controversial. Although one might think that children with prelingual profound deafness have most to gain from implantation, these patients are the most difficult to rehabilitate postoperatively because they have no previous experience of sound. In children with normal hearing speech develops during the first 5 years of life;7 it seems that after the age of 7 the central nervous system is no longer able readily to acquire speech perception. Experience with implants in prelingually deaf individuals lends support to this view, but it must be borne in mind that an implant does not give normal hearing and that the degree of acquisition of speech discrimination varies from patient to patient. Theoretically, however, the ideal time for implantation in childhood would be during the first 3 years of life. The drawbacks are the difficulty in establishing that a child of that age is deaf enough to be
