HEPATORENAL SYNDROME
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1156 HEPATORENAL SYNDROME SIR,—Among the many disasters which may befall the pa- tient with liver disease simultaneous liver and kidney failure is particularly distressing. We were pleased, therefore, to read your editorial on the hepatorenal syndrome (April 30, p. 940). The problem "means many things to many people. Attempting to elucidate the pathogenesis of the hepatorenal syndrome from the literature is like trying to catch a will of the wisp".’ You were right to emphasise the possible importance of endotoxaemia in the setiology of renal impairment in cirrhosis and obstructive jaundice. We have studied renal function and other factors possibly affecting the outcome of surgery in pa- tients with obstructive jaundice and in a series of age-matched controls.’, Our observations support the endotoxin theory. Thus a significant rise in preoperative serum concentrations of fibrin(ogen) degradation products was found only in patients with obstructive jaundice. 80% of these patients died within a month of surgery, primarily from overwhelming infection but often associated terminally with renal impairment. Other adverse preoperative features in these patients were infection, hypoalbuminxmia, old age, and a low glomerular filtration- rate. The role of endotoxaemia in renal failure associated with obstructive jaundice has also been highlighted by the studies of Bailey4 in patients and in rats with bileduct obstruction. Further studies on this problem and on methods of preopera- tive patient preparation aimed at preventing postoperative renal failure will be of great importance in the management of obstructive jaundice. While we agree with you about the importance of endotoxin in the production of acute renal failure in liver disease, we can- not agree that "Kidney structure is remarkably normal". Sig- nificant structural changes do occur at electronmicroscopic level in kidneys of patients with cirrhosis or obstructive jaun- dice. We have studied rats with chronic bileduct obstruction of, on average, 26 days’ duration. Electronmicroscopy of the glo- meruli showed increased activity of both epithelial and endo- thelial cells with prominent rough endoplasmic reticulum and dense packing of organelles. There were fewer fenestrations of endothelial cells. Clearance and kidney micropuncture studies in these rats suggest diminished glomerular permeability, although whole-kidney and superficial single-nephron glomer- ular filtration-rates were not significantly different from those in control sham-operated rats. Choledochoenterostomy reversed the functional changes. Less is known about the distribution of renal blood-flow in obstructive jaundice than about this flow in cirrhosis. The paper you cite5 refers only to cirrhosis. To our knowledge the only study of the distribution of blood-flow in obstructive jaun- dice is that of Bloom et al. in baboons where bileduct ligation of 2 weeks’ duration revealed no evidence of a fall in outer cor- tical blood-flow althought the ratio of inner cortical to outer medullary flow was increased. In our rats with chronic bileduct ligation renal blood-flow, measured by the clearance and extraction of p-aminohippurate was, to our surprise, signifi- cantly greater than in control rats. None of these animals, however, had a significantly lowered whole-kidney or single- nephron glomerular filtration-rate, although their blood-ureas were significantly raised. While endotoxasmia is especially important in animals with hepatobiliary disease of the cirrhotic or obstructive variety, other factors may still play a part. In rats with bileduct 1. Conn, H. O. Gastroenterology, 1973, 65, 321. 2. Allison, M. E. M., Moss, N. G., Fraser, M., Lloyd-Jones, W., Ryan, C. J., Dobbie, J. W., Kennedy, A. C., Blumgart, L. H. VIth int. Cong. Nephrol. 1975, p. 106. 3. Allison, M. E. M., Moss, N. G., Fraser, M., Lloyd-Jones, W., Ryan, C. J., Dobbie, J. W., Kennedy, A. C., Blumgart, L. H. Br. J. Surg. 1975, 62, 653. 4. Bailey, M. E. ibid. 1976, 63, 774. 5. Epstein, M., Berk, D. P., Hollenberg, N. K., Adams, D. F., Chalmers, T. C., Abrams, H. L., Merrill, J. P. Am. J. Med. 1970, 49, 175. 6. Bloom, D. S., Bomzon, L., Rosendorff, C., Scriven, D. R. L. Clin. Sci. 1974, 47, 3P. obstruction a 30 min period of hypotension per se did not - cause acute renal failure.2,3,7 We suggest that some other fac- tor, in addition to endotoxsemia, probably related to the sym- pathetic nervous system, may be of importance. University Departments of Medicine and Surgery, Royal Infirmary, Glasgow G4 0SF MARJORIE E. M. ALLISON L. H. BLUMGART C. D. FORBES C. R. M. PRENTICE ORGANIC ACIDS IN REYE’S LIKE SYNDROME: SIMILARITIES WITH JAMAICAN VOMITING SICKNESS SIR,-Encephalopathy and fatty degeneration of the viscera in infants and children (Reye’s syndrome) has been widely reported since the original description by Reye and his col- leagues, and a consistent clinical, biochemical and pathologi- cal picture has evolved from these reports.9, 10 There is a consid- erable variation, however, in the incidence, presentation, and severity of the disease, and the aetiology, particularly in in- fants, is unclear.’ The disease has been associated with viral infections, aflatoxins, and other causes, and it has been sug- gested that the syndrome may represent the effects of many different setiological factors acting on the same or common metabolic pathways and thereby leading to similar results. The similarities of Reye’s syndrome and the vomiting sickness of Jamaica (J.v.s.), or ackee poisoning, have also been noted" Tanaka et al.’2 have reported the biochemical investigation of two siblings with j.v.s. and included detailed organic-acid analysis that demonstrated the setiology of the disease (hypo- glycin or L-ot-aminomethylenecyclopropylpropionic acid toxi- city) and also the dissimilar findings in patients with Reye’s syndrome. Identical twins seen at Northwick Park Hospital had a Reye’s like syndrome associated with an adenovirus infection." We have analysed urinary organic acids in the disease by quan- titative extraction techniques, gas-liquid chromatography, and gas-chromatography/mass-spectrometry. The children (boys) presented at age 16 months with severe hypoglyceemia, coma, vomiting, and diarrhoea for 30 h. One child died before admission to hospital and urine was obtained post mortem. The survivor was treated with intravenous glu- cose and recovered rapidly; he was taking normal food within 4 days of admission. Urinary organic acids from both siblings were examined on the day of admission and showed a strik- ingly abnormal pattern, with raised concentrations of adipic, 4-hydroxyphenylacetic, and suberic acids in particular and also of one previously unreported urinary organic acid that has been provisionally identified using gas-chromatography/high- resolution mass spectrometry as 4-hydroxy-3-methylpentanoic acid. Other acids detected at increased concentrations are listed in the table where they are compared with those reported in j.v.s. and Reye’s syndrome. There was no evidence for lactic or pyruvic aciduria, and levels of tricarboxylic-acid-cycle metabolites were greatly reduced. Recovery in the surviving sib was accompanied by a rapid return of the urinary organic-acid pattern to normal, the remaining abnormal acids, adipic and suberic, being only slightly raised after 2 days and absent within a week of admis- sion. The table illustrates the close similarities of the organic-acid patterns in these cases with those in j.v.s., although there are some differences, suggesting a slightly different aetiology. 7. Allison, M. E. M., Moss, N. G., Fraser, M., Ryan, C. J., Dobbie, J. W., Ken- nedy, A. C., Blumgart, L. H. Kidney Int. 1975, 8, 338. 8. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 749. 9. Mowat, A. P. Archs Dis. Childh. 1973, 48, 411. 10. Lancet, 1976, ii, 183. 11. Lowry, M. F. in Hypoglycin (edited by E. A. Kean); p. 45. New York, 1975. 12. Tanaka, K., Kean, E. A., Johnson, B. New Engl. J. Med. 1976, 295, 641. 13. Whitelaw, A., Davies, H., Parry, J. Lancet, 1977, i, 361.
Transcript of HEPATORENAL SYNDROME
1156
HEPATORENAL SYNDROME
SIR,—Among the many disasters which may befall the pa-tient with liver disease simultaneous liver and kidney failure isparticularly distressing. We were pleased, therefore, to readyour editorial on the hepatorenal syndrome (April 30, p. 940).The problem "means many things to many people. Attemptingto elucidate the pathogenesis of the hepatorenal syndromefrom the literature is like trying to catch a will of the wisp".’You were right to emphasise the possible importance of
endotoxaemia in the setiology of renal impairment in cirrhosisand obstructive jaundice. We have studied renal function andother factors possibly affecting the outcome of surgery in pa-tients with obstructive jaundice and in a series of age-matchedcontrols.’, Our observations support the endotoxin theory.Thus a significant rise in preoperative serum concentrations offibrin(ogen) degradation products was found only in patientswith obstructive jaundice. 80% of these patients died within amonth of surgery, primarily from overwhelming infection butoften associated terminally with renal impairment. Otheradverse preoperative features in these patients were infection,hypoalbuminxmia, old age, and a low glomerular filtration-rate. The role of endotoxaemia in renal failure associated withobstructive jaundice has also been highlighted by the studiesof Bailey4 in patients and in rats with bileduct obstruction.Further studies on this problem and on methods of preopera-tive patient preparation aimed at preventing postoperativerenal failure will be of great importance in the management ofobstructive jaundice.
While we agree with you about the importance of endotoxinin the production of acute renal failure in liver disease, we can-not agree that "Kidney structure is remarkably normal". Sig-nificant structural changes do occur at electronmicroscopiclevel in kidneys of patients with cirrhosis or obstructive jaun-dice.We have studied rats with chronic bileduct obstruction of,
on average, 26 days’ duration. Electronmicroscopy of the glo-meruli showed increased activity of both epithelial and endo-thelial cells with prominent rough endoplasmic reticulum anddense packing of organelles. There were fewer fenestrations ofendothelial cells. Clearance and kidney micropuncture studiesin these rats suggest diminished glomerular permeability,although whole-kidney and superficial single-nephron glomer-ular filtration-rates were not significantly different from thosein control sham-operated rats. Choledochoenterostomyreversed the functional changes.
Less is known about the distribution of renal blood-flow inobstructive jaundice than about this flow in cirrhosis. The
paper you cite5 refers only to cirrhosis. To our knowledge theonly study of the distribution of blood-flow in obstructive jaun-dice is that of Bloom et al. in baboons where bileduct ligationof 2 weeks’ duration revealed no evidence of a fall in outer cor-tical blood-flow althought the ratio of inner cortical to outermedullary flow was increased. In our rats with chronic bileductligation renal blood-flow, measured by the clearance andextraction of p-aminohippurate was, to our surprise, signifi-cantly greater than in control rats. None of these animals,however, had a significantly lowered whole-kidney or single-nephron glomerular filtration-rate, although their blood-ureaswere significantly raised.
While endotoxasmia is especially important in animals withhepatobiliary disease of the cirrhotic or obstructive variety,other factors may still play a part. In rats with bileduct
1. Conn, H. O. Gastroenterology, 1973, 65, 321.2. Allison, M. E. M., Moss, N. G., Fraser, M., Lloyd-Jones, W., Ryan, C. J.,
Dobbie, J. W., Kennedy, A. C., Blumgart, L. H. VIth int. Cong. Nephrol.1975, p. 106.
3. Allison, M. E. M., Moss, N. G., Fraser, M., Lloyd-Jones, W., Ryan, C. J.,Dobbie, J. W., Kennedy, A. C., Blumgart, L. H. Br. J. Surg. 1975, 62,653.
4. Bailey, M. E. ibid. 1976, 63, 774.5. Epstein, M., Berk, D. P., Hollenberg, N. K., Adams, D. F., Chalmers, T. C.,
Abrams, H. L., Merrill, J. P. Am. J. Med. 1970, 49, 175.6. Bloom, D. S., Bomzon, L., Rosendorff, C., Scriven, D. R. L. Clin. Sci. 1974,
47, 3P.
obstruction a 30 min period of hypotension per se did not-
cause acute renal failure.2,3,7 We suggest that some other fac-
tor, in addition to endotoxsemia, probably related to the sym-pathetic nervous system, may be of importance.
University Departments of Medicineand Surgery,
Royal Infirmary,Glasgow G4 0SF
MARJORIE E. M. ALLISONL. H. BLUMGARTC. D. FORBESC. R. M. PRENTICE
ORGANIC ACIDS IN REYE’S LIKE SYNDROME:SIMILARITIES WITH JAMAICAN VOMITING
SICKNESS
SIR,-Encephalopathy and fatty degeneration of the viscerain infants and children (Reye’s syndrome) has been widelyreported since the original description by Reye and his col-leagues, and a consistent clinical, biochemical and pathologi-cal picture has evolved from these reports.9, 10 There is a consid-erable variation, however, in the incidence, presentation, andseverity of the disease, and the aetiology, particularly in in-fants, is unclear.’ The disease has been associated with viralinfections, aflatoxins, and other causes, and it has been sug-gested that the syndrome may represent the effects of manydifferent setiological factors acting on the same or commonmetabolic pathways and thereby leading to similar results. Thesimilarities of Reye’s syndrome and the vomiting sickness ofJamaica (J.v.s.), or ackee poisoning, have also been noted"Tanaka et al.’2 have reported the biochemical investigation oftwo siblings with j.v.s. and included detailed organic-acidanalysis that demonstrated the setiology of the disease (hypo-glycin or L-ot-aminomethylenecyclopropylpropionic acid toxi-city) and also the dissimilar findings in patients with Reye’ssyndrome.
Identical twins seen at Northwick Park Hospital had a Reye’slike syndrome associated with an adenovirus infection."We have analysed urinary organic acids in the disease by quan-titative extraction techniques, gas-liquid chromatography, andgas-chromatography/mass-spectrometry.The children (boys) presented at age 16 months with severe
hypoglyceemia, coma, vomiting, and diarrhoea for 30 h. Onechild died before admission to hospital and urine was obtainedpost mortem. The survivor was treated with intravenous glu-cose and recovered rapidly; he was taking normal food within4 days of admission. Urinary organic acids from both siblingswere examined on the day of admission and showed a strik-ingly abnormal pattern, with raised concentrations of adipic,4-hydroxyphenylacetic, and suberic acids in particular andalso of one previously unreported urinary organic acid that hasbeen provisionally identified using gas-chromatography/high-resolution mass spectrometry as 4-hydroxy-3-methylpentanoicacid. Other acids detected at increased concentrations are
listed in the table where they are compared with those reportedin j.v.s. and Reye’s syndrome.
There was no evidence for lactic or pyruvic aciduria, andlevels of tricarboxylic-acid-cycle metabolites were greatlyreduced. Recovery in the surviving sib was accompanied by arapid return of the urinary organic-acid pattern to normal, theremaining abnormal acids, adipic and suberic, being onlyslightly raised after 2 days and absent within a week of admis-sion.The table illustrates the close similarities of the organic-acid
patterns in these cases with those in j.v.s., although there aresome differences, suggesting a slightly different aetiology.
7. Allison, M. E. M., Moss, N. G., Fraser, M., Ryan, C. J., Dobbie, J. W., Ken-nedy, A. C., Blumgart, L. H. Kidney Int. 1975, 8, 338.
8. Reye, R. D. K., Morgan, G., Baral, J. Lancet, 1963, ii, 749.9. Mowat, A. P. Archs Dis. Childh. 1973, 48, 411.
10. Lancet, 1976, ii, 183.11. Lowry, M. F. in Hypoglycin (edited by E. A. Kean); p. 45. New York, 1975.12. Tanaka, K., Kean, E. A., Johnson, B. New Engl. J. Med. 1976, 295, 641.13. Whitelaw, A., Davies, H., Parry, J. Lancet, 1977, i, 361.
