Recent advances in the medical aspects of liver disease are reviewed,  especially in the areas of viral hepatitis, chronic aggressive hepatitis and  cirrhosis

Saunders, S.J.

English

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1146 S.-A. MEDIESE TYDSKRIF 23 Oktober 1971Progress in Medical Aspects of Liver DiseaseS. J. SAUNDERS, M.D., F.R.C.P., F.C.P. (S.A.), Professor of Medicine, University of Cape Town; Liver Re-search Group and Liver Clinic, Groote Schuur HospitalSUMMARYRecent advances in the medical aspects of liver diseaseare reviewed, especially in the areas of viral hepatitis,chronic aggressive hepatitis and cirrhosis.S. Afr. Med. l., 45, 1146 (1971).It is hardly possible to review adequately the many de-velopments in liver disease in recent years and I intendto confine myself to a few specific areas which seem tobe of particular importance.VIRAL HEPATITISGood evidence for the viral aetiology of this disease isaccumulating and we have also obtained a ~etter under-standing of 'infectious' hepatitis and 'serum' hepatitis. Thisis largely due to the work at the Willowbrook School wheretwo infectious agents have been identified: the short in-cubation agent (30 - 38 days) MS-l and the long incubationagent (41 - 108 days) MS-2.' This important study not onlyclearly defines the two types of infective agents but alsoshows that they each have immunological identity, i.e.infection with one strain does not confer immunity to theother. It was also shown that hepatitis can be spread bycontact, and that the MS-2 type, i.e. serum hepatitis, whileusually transmitted through the skin with contaminatedmaterial on needles, etc., and although not highly infectiousby contact, is communicable and infective by mouth. Theexistence of two types of orally transmissible hepatitisalso explains why some patients get second attacks ofhepatitis.Linked with this important information has been theexplosion of interest in the Australia antigen or bettertermed Hepatitis Associated Antigen (HAA).In 1965, Blumberg and his colleagues' were working inPhiladelphia on the development of antibodies againsthuman serum lipoproteins and found that there was aprecipitin which reacted with an antigen in a single serumwhich came from an Australian Aborigine. A relationshipwas recognized between HAA and leukaemia, Down'ssyndrome, lepromatous leprosy and hepatitis. The lastassociation proved to be the significant one. Reports on theincidence of HAA vary from 95% in post-transfusionhepatitis and 47% in infectious hepatitis to 13 % or 0%respectively! The variable results are dependent upondiffering techniques and methods of isampling. Early fre-quent blood samples give the highest number of positiveresults. It is of interest that in a subsequent Willowbrookstudy HAA was found only in patients with MS-2infection!"Its relationship to chronic liver disease has also givenconflicting results. Wright and his co-workers from Yale·found the antigen persisting for months or years in 7 of 14cases of unresolved hepatitis, 4 of 15 cases of subacutehepatic necrosis progressing to posthepatitic cirrhosis, and6 of 24 cases of chronic active hepatitis. In London, Foxand his colleagues' could not detect HAA in 32 patientswith active chronic hepatitis. As new data become availablesimilar striking differences are being found!Hepatitis has developed in patients receiving HAA-positive blood but it is noteworthy that HAA-positive post-transfusion hepatitis has followed transfusion with HAA-negative blood." More recently the incidence of hepatitisafter the administration of HAA-positive blood has beenreported as 70%: while only 4 cases were seen in 69patients who received HAA-negative bloOd."There is still no direct evidence that HAA is an infec-tious agent. It seems unlikely that it represents the virusparticles of hepatitis virus, but it is probably closely relatedto the causative agent.Clinically there has been an increased awareness of thesyndromes which may follow on viral hepatitis. It iscommon for patients to experience mild chronic ill-healthfor some months after an attack of viral hepatitis, and it isimportant to recognize that the great majority of thesepatients make a complete recovery. It is not uncommon forthe serum globulin levels to remain elevated for some time,and for the patient to have a persistent mild unconjugatedhyperbilirubinaemia. These have no adverse prognosticsignificance, and the latter may well represent mild in-creased haemolysis, or a temporary defect in bilirubintransport across the liver cell membrane. Indeed, Conrad'·has recently emphasized the occurrence of increasedhaemolysis in patients with viral hepatitis. Three of hispatients had a persistent reticulocytosis and an elevatedunconjugated bilirubin in the plasma for more than ayear after recovery, while in 68 patients there was a sig-nificant decrease in the packed cell volume in the secondor third week of the illness. He also noted an increase incirculating reticulocytes in these patients during the thirdand fourth week.In recent years, a group of patients has been clearlyrecognized who have persistently or intermittently elevatedserum transaminase levels after viral hepatitis. The term'transaminitis' has been used and these abnormalities maypersist for up to 3 years after the original illness.n .,.Becker et al." have studied 20 patients followed up for2 - 14 years after viral hepatitis. Some of the patients hadlost weight and a few had had mild recurrent abdominalpains. Eight had enlarged livers, but there was no other23 October 1971 S.A. MEDICAL JOURNAL 1147evidence of chronic liver disease. During the first year ofthe illness, laboratory tests were of no value in differentiat-ing these patients with persistent hepatitis ('transaminitis')from those with chronic aggressive ('active') hepatitis. Thetransaminase levels were considerably elevated, but afterthe second year fluctuated at a lower level. Throughoutthe course alkaline phosphatase and bilirubin levels werenot diagnostically helpful, being either normal or slightlyelevated. Globulin levels during the first year werevariable. HAA was negative in 14 sera tested.The characteristic portal tract lymphocytic infiltrationwith preserved architecture and mild piece meal necrosiswere found histologically. Serial biopsies in 12 patientsshowed no evidence of progression to chronic aggressivehepatitis. At a follow-up examination on an average of6 years from the onset, 16 of the 20 patients were welland without clinical evidence of liver disease, and in 3patients transaminase levels were still mildly elevated. Tenpatients received corticosteroids for either prolongedjaundice or persistently elevated transaminase levels. How-ever, there was no difference in the course between thetreated and untreated patients. Chronic persistent hepatitisis a relatively benign entity that must be distinguished fromchronic aggressive hepatitis. Although there is no adequatelong-term follow-up, present evidence suggests that theprognosis is good in persistent hepatitis. The liver biopsyis critical in distinguishing it from chronic aggressivehepatitis.CHRONIC AGGRESSIVE HEPATITISChronic aggressive hepatitis (active chronic hepatitis)",l.is a well-recognized syndrome, the aetiology of whichremains unknown. While there is evidence for an immuno-logical, J!lossibly autoimmunological basis for this disease,there is no proof of what Popper" has called 'autoaggres-sion'. Chronic aggressive hepatitis affects subjects of bothsexes and of all ages but is characteristically seen in youngwomen. There is intermittent jaundice, hepatosplenomegalyand eventual liver failure. Gamma-globulin levels tend tobe very high and the transaminase levels are often ele-vated. Other systems are often involved, e.g. thyro~ditis,ulcerative colitis, renal tubular acidosis, arthritis andarteritis may all occur. Smooth-muscle antibodv is charac-teristically present in the plasma, but may be present inother forms of liver disease.A great deal of interest in the role of the immunesystem in liver disease has been stimulated by the recog-nition of chronic aggressive hepatitis, and has led tostudies of other circulating antibodies, notably antimito-chondrial antibodies in primary biliary cirrhosis, of-serumimmunoglobulins and delayed hypersensitivity in liverdisease, and has resulted in immunosuppressive therapybeing assessed in the treatment of chronic aggressivehepatitis in particular. Sherlock has recently published anexcellent review of this important aspect of liver disease."The detection of the LE cells in some patients withchronic aggressive hepatitis raised the possibility of anaetiological association with systemic lupus erythematosus.While this has not been established there is an increasingawareness of liver lesions in systemic lupus erythemato-sus.'"CIRRHOSISThere has been a better understanding of the aetiology ofportal hypertensionc'O and of the greatly increased lym-phatic flow and of the alteration of bile flow in cirrhosis.'"Jaundice in cirrhosis is usually cholestatic and in mostcases there is no extrahepatic obstructive cause. It isprobably due to a defect in the liver cells themselves asin cholestatic hepatitis. There is an alteration of organellesaround the bile canaliculus which is dilated, while itsmicrovilli are altered." This morphological picture isthought to be an expression of the interference withsecretion of bile salts, which results in a disturbance ofmicelle formation with consequent defective formationof bile. It was previously believed that the changes in thecholangioles were secondary to the liver cell pathology.It is interesting that in the absence of jaundice, bile flowmay be increased in cirrhosis presumably as a result ofincreased intrasinusoidal pressure."Our understanding of the pathogenesis of cirrhosis haslaid much greater emphasis on the role of the necrosisrather than on fatty change. Indeed, while there is littledoubt that alcohol abuse leads to cirrhosis and almostalways causes fatty change, there is no evidence thatfatty change itself results in cirrhosis. Necrosis is thelink to cirrhosis and Popper has described the differentforms of necrosis which are its possible precursors:"necrosis produced by known exogenous factors such asalcohol, anoxic necrosis, cholestatic necrosis and piece-meal necrosis. Necrosis is diagnosed histologically butt1:J.e biocl,emical derangements must significantly precedetl-Je microscopical changes. There is no certainty as towhere the process begins but the early conception ofmitochondrial damage remains a possibility." Peroxidativechanges may also be important""" either through involve-ment of phospholipids particularly in membranes or as aresult of the formation of free radicals.There have been advances in our understanding ofcollagen metabolism and of the pathogenesis of fibrosis.Formerly the consequences of collapse after parenchymaIdestruction received emphasis but it is now realized thatnew fibre formation plays a vital role. This represents abalance between stimulation of fibrob!asts, maturationand deposition of fibres and catabolism of fibres, thewhole process probably being stimulated by hepatocellularinjury. Damage to liver cells as a result of fibrosis may inturn stimulate more fibrosis and may prove to be a moreimportant mechanism in the development of cirrhosisthan aTJy immunological one."A better understanding of the pathogenesis of thecomplications of cirrhosis has resulted in improvementin therapy of ascites and encephalopathy. Renal failure(hepatorenal syndrome) in cirrhosis has become one ofthe common causes of death. It is characterized by azo-taemic oliguria and urine with a low sodium content andhigh osmolality. These kidneys may function normallyif transplanted" and the dysfunction does not seem toresult from changes in systemic blood volume'" or cardiac1148 S.-A. MEDIESE TYDSKRIF 23 Oktober 1971output"" but seems to be due to circulatory changes withinthe kidneys, possibly with vasoconstriction.'O,3l The patho-genesis of this syndrome may not be the same in allpatients and in some plasma expansion may be effectivetreatment."OTHER DEVELOPMENTSThe demonstration that a number of pharmacologicalagents are capable of inducing microsomal enzymes is ofgreat potential therapeutic importance. This knowledgehas been used clinically to lower unconjugated hyper-bilirubinaemia by giving phenobarbitone. More recently,dicophane has been used for the same reason in a boyaged 17 years."" This compound has still to be proved tobe safe from the toxic point of view and indeed convinc-ing demonstration of the induction of glucuronyl-transferase has not been achieved in the case of eitherdrug. Of interest also has been the demonstration thatethanol can be metabolized by a microsomal oxidizingsystem," but the importance of this in ethanol metabolismremains to be established.'5 Induction of enzymes mayplay a role in determining the toxicity of some com-pounds. Carbon tetrachloride is much less lethal in ratspreviously fed a low-protein diet and this effect is re-versed by pretreating them with phenobarbitone or DDT."This is because the toxicity of CCl. is dependent upon itsbeing metabolized by the microsomal hydroxylating en-zymes and a low-protein diet reduces the activity of theenzyme system to a third or less than normal in 4 days.These drug metabolizing enzymes are usually thought ofas 'detoxicating' enzymes and indeed often do act in thatway. It is clear that in some instances the reverse mayoccur.Further studies by Arias and his colleagues on thetwo hepatic cytoplasmic protein fractions Y and Z haveshown that it is very likely that these proteins are im-portant in the uptake of bilirubin and bromsulphthaleinby the liver cell.'" These substances are preferentiallybound to the Y and Z proteins within the cell. The sameworkers have produced evidence to suggest that a lack ofY protein may play a role in Gilbert's syndrome andneonatal jaundice."'" These proteins may prove to be offundamental importance in the transport of many sub-stances across the liver cell membrane and within itscytoplasm.Major advances made in bilirubin and bile salt meta-bolism have been reviewed recently."'"The study of alpha-feto-protein has been very reward-ing."'" In primary liver cell carcinoma it is present in30% of Caucasians and in 60 - 70% of non-Caucasians'o,,'Five patients with cirrhosis and primary hepatoma havehad HAA in the plasma'" and two of these had alpha-feto-protein in the plasma as well. It is possible that viralhepatitis is potentially precancerous as suggested bySteiner45 and others some time ago.The treatment of acute liver failure by exchange trans-fusion, pig-liver perfusion and cross-circulation has beenclosely studied in a number of centres, particularly inCape Town.... While these procedures may improve thepatient from the neurological standpoint there is no clearevidence that they prolong life. There is a better under-standing of the many complications of fulminant hepatitisand a greater realization of the importance of liver cellregeneration in prognosis."Liver disease has become the fourth or fifth most fre-quent cause of death in the USAIS and is very commonin South Africa. Recent advances in liver disease havenot, on the whole, led to more rational treatment-whichis, indeed, conspicuously lacking. The identification andculture of the hepatitis virus and a clear understanding ofthe causes of cryptogenic cirrhosis and primary livercancer remain three of the most important unansweredquestions in this field.REFERENCESI. Krugman, S., GiJes, J. P. and Hammond, J. (1967): J. Amer. Med.Assoc., 200, 365.2. Blumberg, B. S., Alter, H. J. and Wisnich, S. E. (1965): Ibid., 191,541.3. Shulman, N. R. (1970): Amer. J. Med.; 49, 669.4. Giles, J. P., McColium, R. W., Bemdtson, L. W. and Krugman, S.(1969): New. Engl. J. Med., 281, 119.5. Prince, A. M., Hangrove, R. L., Szmuness, W., Chemkin, C. E.,Fontana, V. J. and Jeffries, G. H. (1970): Ibid., 282, 987.6. Wright, R., McCollum, R. W. and Kaltskin, G. (1969): Lancet, 2, 117.7. Fox, R., Niazi, S. B. and Sherlock, S. (1969): Ibid., 2, 609.8. O'wchi', K. and Murakarri, S. (1968): Vox Sang, 15, 374.9. G"cke, D. J., Greenberg, H. B. and Kowey, N. B. (1969): Lancet, 2,248.10. Conrad, M. E. (1969): Gut, 10, 516.11. Gallagher, N. D. and Goulston, S. J. (1962): Brit. Med. J., I, 906.12. Reisler, D. M., Strong, W. B. and Mosley, J. W. (1967): J. Amer.Med. Assoc., 202, 37.n. Levine, R. A. and Ranek, L. (1970): Gastroent., 58, 371.14. Becker, M. D., Bapiste, A., Scheuer, P. J. and Sherlock, S. (1970):Lancet, I, 53.15. Sherlock, S. (1966): Acta Med. Scand. Suppl., 445, 426.16. Whittingham, S., MacKay, I. R. and Irwin, J. (1966): Lancet, I, 1333.17. Popper, H. and Udenfriend, S. (1970): Amer. J. Med., 49, 707.18. Sherlock, S. (1970): Ibid., 49, 693.19. Annotation (1970): Lancet, I, 1095.20. Reynolds, T. B., Ito, S. and Watsuki, S. (1970): Amer. J. Med., 49,649.21. Pop,er, H. and Orr, W. (1970): Scan. J. Gastroent., 5, 203.22. Poer.er. H. ('968): Ann. Rev. Med., 19, 39.23. Lentlnll, J., Reynolds, T. B. and Donovan, A. J. (1970): Surg. Gynec.Obstet., 130, 243.24. Judah, J. D .. McLean, A. E. M. and Lean, E. K. (1970): Amer. J.Med., 49, 609.25. Recknagel, R. O. (1967): Pharmacol. Rev., 19, 145.26. Diangami, M. U., Baccino, F. M. and Compoiti, M. (1966): Lab.Invest.. 15. 149.27. Koopel, M. H., Cobum, 1. W., Mims, M. M., Goldstein, H., Boyle,J. D. and Rubini, M. E. (1969): New Engl. J. Med., 280, 1367.28. Lieberrnan, F. L., Ito, S. and Reynolds, T. B. (1969): 1. Clin. Invest.,4R, 975.29. Gould, L., Shariff, M., Zahir, M. and Dilieto, M. (1969): Ibid., 48,860.30. B,ldus. W. P. (1969): Mod. Treat., 6, 191.31. Schroeder, E. T., Shear, L., Sangcetta, S. M. and Gabuzda, G. J.(!968): Amer. J. Med., 43, 887.32. Trestani, F. E. and Cohn, J. M. (1967): J. Clin. Invest .. 46, 1894.33. Thompson, R. P. H., Stathers, G. M., Pilcher, C. W. T., MacLean,A. E. M., Robinson, J. and Will;ams. Roger (1969): Lancet, 2, 4.34. Lieber, C. S. and Rubin, E. (1969): New Engl. J. Med., 280, 705.35. Te"hly T. R., Tienelli, F. and Watkins, W. D. (1969): Science, 166,627.36. l.evi. A. J., Gatmaitan, Z. and Arias, L M. (1969): J. Clin. Invest.,48. 2156.31. Idem (1969): Lancet. 2, 139.:l8. Hem (1969): Paed. Res., 3. 105.39. Fleischner, G. and Arias, I. M. (1970): Amer. J. 1I.1ed .• 49, 576.40. r."ey, M. C. and Small, D. M. (19701: lbid .. 49, 590.41. Purves, L. R., van der Merwe, E. and Bersohn, I. (1970): S. Afr. Med.J .. 42, 1138.42. Purves, L. R., van der Merwe, E. and Bersohn, I. (1970): Ibid., 44,1264.43. Alpert, M. E., Uriel, J. and de Nechaud, M. (1968): New Engl. J.Med.,. 278. 984.44. Sherlock, S.. Fox, R. A., Niazi, S. P. and Scheuer, P. J. (1970):T,ancet, T. 1243.45. Steiner, P. E. (1961): Unio. Int. Contra Cancrum Acta., 17, 798.46. Saunders. S. J., Bosman, S. C. W., Barnard, C. N. and Terblanche,J. (1969): Current Concepts, 2, 161.47. Saunders. S. J., Hickman, R., Goodwin, N. E. and Terblanche, J.(971): Proc. 4th World Congress Gastroent, (in the press).48. Popper, H. (1970): Amer. J. Med., 49, 573.

Progress in medical aspects of liver disease

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Progress in medical aspects of liver disease

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