Symposium on Diseases of the Liver
Hepatitis in the Drug Abuser Leonard B. Seeff, M.D.*
Drug addiction has increased alarmingly in recent years to almost epidemic proportions. 19. 39. 69 Changing social mores and the relative ease of travel for young people have permitted dissemination of illicit drug use throughout the United States and Europe. In the United States the problem has been further aggravated by the high rate of drug abuse among the military. The ease of access to narcotic drugs by troops in Asia and Europe has precipitated a drug addiction crisis among enlisted men.33. 66 On their return to civilian life, they have swelled the ranks of the drug-using population in this country. Habitual parenteral drug users are subject to a number of potentially serious infectious complications,t°' 52 resulting from the common use of unsterile needles and syringes. In 1950, Steigmann et al.67 first drew attention to the association between parenteral drug abuse and "serum" hepatitis. Numerous similar observations have followed from the United States2. 3. 17. 50. 56. 61 and other parts of the world.4. 39. 53. 54. 58. 60. 69 Indeed, in 1967, Louria et al.52 reported that serum hepatitis was the foremost infectious complication requiring the admission of addicted patients to the medical services of municipal hospitals in New York City. Some investigators, however, have been unwilling to accept the fact that hepatitis is the major cause for the hepatic injury in drug addicts, and have incriminated toxic effects of the narcotic drugs, or contaminants injected with the drug. The suggestion that heroin and cocaine,53 opiates,21 methadone,74 amphetamines,s and marijuana43 might be responsible for the liver injury has not been supported by carefully conducted studies of some of these drugs. 7. 31. 46. 51 It has also been suggested that malnutrition41 and alcohol68 may play a role in producing hepatic injury in drug users. It cannot be denied that the occasional "hard-core" addict shows evidence of malnutrition, and it has also become evident in recent years that narcotic addicts are willing to extend their addiction to include alcohol. However, fatty metamorphosis and alcoholic hyaline seem to be relatively infrequent and insignificant findings in liver specimens of drug addicts. Perhaps the most compelling evidence in support of viral hepatitis as the major cause for the liver disease in the drug-using population is provided by the accumulated data of the hepatitis B antigen (HBsAg). ·Assistant Chief, Medical Service, Veterans Administration Hospital; Assistant Professor of Medicine, Georgetown University School of Medicine, Washington, D.C.
Medical Clinics of North America- Vol. 59, No. 4, July 1975
843
844
LEONARD
B.
SEEFF
This antigen has been detected in 50 to 75 per cent of addicts with acute hepatitis,l1· 39. 54.76 and is reported to be present in asymptomatic drug addicts with a frequency 10 to 100 times that of the general population Cl to 10 per cent)Y' 40, 70 It may therefore be assumed that the recent increase in the number of drug users has greatly expanded the hepatitis and HBsAg reservoir in the United States, As a result, drug addicts present an important public health hazard to the community, as well as to other, newly addicted individuals, with whom they share their needles,
EFFECTS ON THE COMMUNITY Changing Epidemiology The epidemic of drug abuse that has swept the United States appears to have dominated the epidemiology of viral hepatitis during the past decade, with a progressive increase in the number of cases reported as "acute infectious or nonspecific" and as "serum" hepatitis between the years 1966 and 1972.9 That drug-associated hepatitis has had an impact on the increasing incidence, seems evident from the greater than 6fold increase in viral B hepatitis that has been noted, accompanied by only a doubling of cases considered to have a diagnosis of viral A hepatitis. Furthermore, previous characteristic epidemiologic patterns of hepatitis have undergone alterations which can be ascribed to the influx of the drug-using population. These are: Ca) the loss of the previously recognized seasonality of reported cases; (b) a change in the preponderance of hepatitis from rural to urban areas; Cc) the change from the previously noted equal frequency of the disease in both sexes to a predominance in males; and (d) a striking change in the age distribution. 22 In 1966 the majority of cases reported as viral B hepatitis involved adults over the age of 30. However, in 1972,80 per cent of cases were reported to be in individuals 15 to 24 years of age. Furthermore, in 1966, posttransfusion hepatitis constituted 55 per cent of the cases reported as hepatitis B, while in 1972, 70 per cent of cases reported as hepatitis B occurred in acknowledged parenteral drug abusers.9 This represents a change from a transfusion-associated disease of older adults in 1966, to a parenteral drug-associated disease of young adults in 1972. Parallel changes also have been noted in Veterans Administration hospitals. Patients with a diagnosis of viral hepatitis increased from a figure of 14.4 per 10,000 in 1965, of whom only 2.2 per cent were 18 to 25 years of age, to 49.1 per 10,000 discharges in 1972,60.9 per cent of whom were in this age group.59 In one VA hospital (Boston, Massachusetts) acknowledged drug abusers constituted only 5 per cent of the hepatitis cases admitted between 1963 and 1967, but 60 per cent of patients admitted with viral hepatitis between 1968 and 1971.62 Impact of Nonparenteral Transmission Until recently, it had been assumed that hepatitis was spread from one addict to another almost exclusively through the sharing of contaminated equipment. In 1967, Krugman et a1. 47 demonstrated under experimental conditions, that MS-2 (viral B) hepatitis could be transmitted orally, and further, that it was mildly contagious to close contacts. Sup-
HEPATITIS IN THE DRUG ABUSER
845
porting evidence for nonparenteral transmission of viral B hepatitis has come from numerous subsequent clinical, serologic and epidemiologic surveys.8, 11, 30, 34, 38, 48, 75 For example, cases of "sporadic" hepatitis (hepatitis without obvious parenteral exposure) have a high incidence (± 50 per cent) of HBsAg. Also, the antigen is almost endemic in certain parts of the world and in institutions for the mentally retarded, under circumstances in which overt parenteral exposure cannot be recognized. Further, it has been noted that close contacts of carriers of HBsAg develop HBsAg, antiHBs or overt hepatitis at a significantly higher rate than contacts of HBsAg-negative controls. The precise mode of transmission is unclear, although it has been speculated that certain body fluids and secretions may be responsible for transmitting the disease. Indeed, the antigen has been demonstrated in saliva and semen,27 feces,25 urine and tears,71 vaginal secretions,15 breast milk,6 and other body fluids. The infectivity of these body fluids, however, is yet to be satisfactorily demonstrated. However, spread through intimate sexual contact now seems likely, supporting the possibility that saliva or semen may well behave as vehicles for transmission. Finally, it has been suggested that airborne transmission of viral B hepatitis may occur,1 and that mosquitoes and other arthropods may act as vectors for the disease. 49
Post-transfusion Hepatitis The high risk of developing post-transfusion hepatitis after receipt of blood from commercial sources is well established.63 , 73 Commercial· blood has been shown to contain HBsAg with a frequency 12 times that of volunteer blood,12 and it is also likely that this type of blood harbors other, as yet undefined, forms of viral hepatitis. 63 Drug users have traditionally been a rich source for commercial blood procurers, and posttransfusion hepatitis has been demonstrated to follow the infusion of blood from addicts.14 In recent years, the practice of purchasing blood from these individuals has been sharply curtailed, but has by no means ceased. Indeed, 50 per cent of patients participating in the V A Cooperative Study of Liver Disease in the Drug Addict admitted to either selling or donating their blood for transfusion purposes in the recent past. 64
Risk to Medical Personnel Physicians, nurses, and technicians are at high risk of developing hepatitis through accidental inoculation while caring for patients with the disease. The growing numbers of hospitalized drug addicts with overt hepatitis, and the often unrecognized HBsAg carrier state of addicts hospitalized for other reasons, increase the risk. Indeed, almost 10 per cent of individuals who have entered a V A cooperative study of "needlestick" hepatitis (designed to evaluate the preventive effect of hepatitis B immune serum globulin) had been exposed to blood from drug addicts. 65
EFFECT ON THE DRUG USER The drug user is a hazard both to the community, and to his fellow addict. The high carrier rate of HBsAg and the high incidence of asymptomatic acute disease, makes every needle-sharing experience, even
846
LEONARD
B.
SEEFF
with apparently normal individuals, a potential episode for transmission of the disease.
Hepatitis While viral hepatitis is the most frequent infectious complication of parenteral drug abuse, it is asymptomatic and anicteric more frequently than overt. The frequency and severity of hepatitis, and the frequency of antigenemia have been reported to be higher in white than in black addicts,76 presumably the result of a greater immunity in members of lower socioeconomic groups than in those from a more affluent background. The onset of illness is usually insidious, and is preceded in almost 25 per cent of patients by a serum-sickness-like syndrome (urticaria, arthralgia, arthritis, angioneurotic edema), considered a result of HBsAg/antiHBs immune complexes.2o Acute hepatitis in the drug addict differs in several respects from that seen in other settings. These include (a) a propensity for multiple bouts; (b) the almost exclusive presence of a specific subtype; (c) certain unusual histologic features; and (d) a significant incidence of progression from acute to chronic hepatitis. Several investigators have reported that multiple episodes of apparent acute hepatitis (as many as 5 separate bouts) occur in 10 to 30 per cent of drug addicts. 26 . 38. 42. 65 Available data42 suggest that only one of these multiple bouts is associated with the HBsAg, permitting the inference that the others are the result of more than one immunologically distinct virus. That some of the bouts may be caused by the hepatitis A virus has been considered to be supported by the finding of high IgM levels in HBsAg-negative hepatitis. 38 Other, presently undefined agents (? virus C), also are suspected. However, distinction of individual bouts of acute hepatitis from reexacerbations of the original illness, may be exceedingly difficult. Documented prolonged periods of normal transaminase values between each apparent acute bout should be a minimal requirement, since it is common for drug addicts to have prolonged fluctuating transaminase abnormalities with histologic features of chronic hepatitis. In the United States, the ay subtype predominates in blood donors who are carriers of the HBsAg,18 while the subtypes ad and ay occur with approximately equal frequency in patients with acute hepatitis. 32 However, drug addicts who develop acute viral B hepatitis have HBsAg of almost exclusively the ay subtype. 24 • 55. 75 This uniformity is thought to result from continued propagation of this single subtype because of the communal living arrangements of some addicts, as well as from the regular sharing of contaminated equipment. The histology of acute hepatitis in the drug user is variable. It ranges from the typical changes of acute hepatitis (lobular disarray, ballooning degeneration, hepatocellular necrosis, acidophilic bodies, widespread inflammation) to quite mild abnormalities (scattered focal necrosis a!ld inflammation). Of particular importance is the fact that drug addicts may demonstrate the clinical and biochemical features of acute hepatitis, with histologic abnormalities strongly suggestive of chronic hepatitis (portal fibrosis, "piecemeal" necrosis, abundant plasma cells). Widening of the portal area and portal fibrosis, with occasional tongue-like projections
HEPATITIS IN THE DRUG ABUSER
847
extending into the parenchyma, is a common finding.35 This presumably represents evidence of previous, often undetected disease. Also common is the evidence of a distorted "limiting plate" and "piecemeal necrosis," a lesion generally considered indicative of chronic active hepatitis. 16 Portal inflammation may be flamboyant, consisting of "round cells," plasma cells and eosinophilic leukocytes. The profusion of plasma cells also may be of concern, because of their association with chronic liver disease. Possible explanations for their abundant presence include the suggestion that they might reflect an exacerbation of a previous acute episode of hepatitis, that they represent an inflammatory response modified by previous bouts of hepatitis from which the individual has recovered, or that they appear in response to long-continued exposure to narcotic drugs or contaminants. Despite the appearance of these disturbing features, the majority of drug addicts with acute hepatitis seem to recover without obvious chronic sequelae. Nevertheless, exaggerated evidence of these abnormalities should signal the need for careful long-term follow-up to include a repeat liver biopsy in the evaluation process. A histologic feature of particular interest to us is the· high frequency, and often the great density, of eosinophilic leukocytes in the portal areas in drug associated acute hepatitis.35 Indeed, eosinophils may be present in sufficient numbers to warrant the consideration of a hypersensitivity drug reaction or even of a parasitic infection. It has been suggested that the narcotic drugs or their contaminants may be responsible for this apparent hypersensitivity response. 29 Another, pathognomonic histologic finding in the drug abuser, is the presence of adventitious material (talc, silica, calcite) in portal macrophage and Kupffer cells.36 When sought with a polarizing lens, these particles may be found in 20 to 30 per cent of biopsies in drug addicts. An important concern is the possible development of chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH), or even of cirrhosis, in asymptomatic drug addicts who mayor may not have biochemical evidence of liver injury. Indeed, 25 per cent of the drug abusers participating in the V A Study 64 biopsied because of persistently abnormal transaminase values, have demonstrated the histologic characteristics of CAH or cirrhosis. Furthermore, data from this study have indicated that CPH and CAH, as diagnosed histologically, could not be distinguished from one another on the basis of clinical or biochemical findings. With the exception of a significantly higher incidence of the HBsAg in those with chronic active hepatitis, other biochemical tests, including serum transaminases, proteins, protein electrophoresis, and immunoglobulins, were found to be similar in the two groups. It is our belief that every drug abuser with persistently abnormal transaminase values (> 3 months), particularly when accompanied by a positive test for the HBsAg, should have a liver biopsy performed. Accurate estimation of the incidence of chronic liver disease as a sequel to acute hepatitis occurring in the drug addict awaits prospective studies. Current data suggest that approximately 12 per cent of patients with acute type B hepatitis develop CPH. Less than one third remain HBsAg positive. Approximately 1 per cent develop chronic active hepatitis and/or cirrhosis. Almost all of this group continue to be positive for HBsAg.57 A high rate of chronicity also may be inferred from studies con-
848
LEONARD
B.
SEEFF
ducted in asymptomatic drug abuse patients. Over 75 per cent of approximately 300 totally asymptomatic drug users participating in the VA drug abuse hepatitis study&' were found to have abnormal SGPT values, 9 per cent were positive for HBsAg, and 87 per cent were positive for antiHBs. Only 5 per cent had no evidence of present or past liver disease. As already noted, 25 per cent of the patients subjected to liver biopsy demonstrated histologic evidence of CAH or cirrhosis. It therefore seems evident that a high proportion of drug addicts have undetected serious chronic liver disease, which may not emerge clinically until many years later. Nonhepatic Disease Drug abusers are prone to develop a number of nonhepatic HBsAgrelated complications, presumably a result of immune complex (HBsAg/antiHBs) formation and deposition. Renal disease (membranoproliferative glomerulonephritis, focal glomerulonephritis, epimembranous glomerulonephritis) with demonstrated deposition of HBsAg, IgM and {3 1C, and which manifests as the nephrotic syndrome, has been reported.44 • 45 Polyarteritis23 and necrotizing angiitis, primarily in metamphetamine users,t3 also have been described. Arthralgias and arthritis, usually occurring during the prodromal period of acute viral B hepatitis, and sometimes associated with urticaria, occurs in as many as 25 per cent of patients:20 Finally, the presence of HBsAg in some patients with primary hepatocellular carcinoma72 has led to the concern that HBV might be an oncogenic virus. To our knowledge, HBsAg-positive primary carcinoma has not been described in a drug addict patient. However, continued, long-term observations are essential before this grave complication can be excluded. CONCLUSION Drug addicts have a high incidence of acute and chronic viral hepatitis. The acute disease in this population is characterized by apparent multiple bouts, only one of which is HBsAg-positive, the presence of HBsAg of the ay subtype, often confusing histologic abnormalities, and a high rate of progression to chronic liver disease. Important chronic liver disease (chronic active hepatitis, cirrhosis) may develop without clinical or biochemical warning, indicating that a liver biopsy is necessary for diagnostic confirmation. As a result of their high incidence of overt and asymptomatic viral hepatitis, and of their high HBsAg-carrier state, drug addicts are potential hazards to their fellow abusers, as well as to the community. ACKNOWLEDGMENT
I wish to thank Dr. Hyman J. Zimmerman for his invaluable help and constructive suggestions during the course of the preparation of this manuscript. Medical Service Veterans Administration Hospital Washington, D.e. 20422
Hepatitis in the Drug Abuser Leonard B. Seeff, M.D.*
Drug addiction has increased alarmingly in recent years to almost epidemic proportions. 19. 39. 69 Changing social mores and the relative ease of travel for young people have permitted dissemination of illicit drug use throughout the United States and Europe. In the United States the problem has been further aggravated by the high rate of drug abuse among the military. The ease of access to narcotic drugs by troops in Asia and Europe has precipitated a drug addiction crisis among enlisted men.33. 66 On their return to civilian life, they have swelled the ranks of the drug-using population in this country. Habitual parenteral drug users are subject to a number of potentially serious infectious complications,t°' 52 resulting from the common use of unsterile needles and syringes. In 1950, Steigmann et al.67 first drew attention to the association between parenteral drug abuse and "serum" hepatitis. Numerous similar observations have followed from the United States2. 3. 17. 50. 56. 61 and other parts of the world.4. 39. 53. 54. 58. 60. 69 Indeed, in 1967, Louria et al.52 reported that serum hepatitis was the foremost infectious complication requiring the admission of addicted patients to the medical services of municipal hospitals in New York City. Some investigators, however, have been unwilling to accept the fact that hepatitis is the major cause for the hepatic injury in drug addicts, and have incriminated toxic effects of the narcotic drugs, or contaminants injected with the drug. The suggestion that heroin and cocaine,53 opiates,21 methadone,74 amphetamines,s and marijuana43 might be responsible for the liver injury has not been supported by carefully conducted studies of some of these drugs. 7. 31. 46. 51 It has also been suggested that malnutrition41 and alcohol68 may play a role in producing hepatic injury in drug users. It cannot be denied that the occasional "hard-core" addict shows evidence of malnutrition, and it has also become evident in recent years that narcotic addicts are willing to extend their addiction to include alcohol. However, fatty metamorphosis and alcoholic hyaline seem to be relatively infrequent and insignificant findings in liver specimens of drug addicts. Perhaps the most compelling evidence in support of viral hepatitis as the major cause for the liver disease in the drug-using population is provided by the accumulated data of the hepatitis B antigen (HBsAg). ·Assistant Chief, Medical Service, Veterans Administration Hospital; Assistant Professor of Medicine, Georgetown University School of Medicine, Washington, D.C.
Medical Clinics of North America- Vol. 59, No. 4, July 1975
843
844
LEONARD
B.
SEEFF
This antigen has been detected in 50 to 75 per cent of addicts with acute hepatitis,l1· 39. 54.76 and is reported to be present in asymptomatic drug addicts with a frequency 10 to 100 times that of the general population Cl to 10 per cent)Y' 40, 70 It may therefore be assumed that the recent increase in the number of drug users has greatly expanded the hepatitis and HBsAg reservoir in the United States, As a result, drug addicts present an important public health hazard to the community, as well as to other, newly addicted individuals, with whom they share their needles,
EFFECTS ON THE COMMUNITY Changing Epidemiology The epidemic of drug abuse that has swept the United States appears to have dominated the epidemiology of viral hepatitis during the past decade, with a progressive increase in the number of cases reported as "acute infectious or nonspecific" and as "serum" hepatitis between the years 1966 and 1972.9 That drug-associated hepatitis has had an impact on the increasing incidence, seems evident from the greater than 6fold increase in viral B hepatitis that has been noted, accompanied by only a doubling of cases considered to have a diagnosis of viral A hepatitis. Furthermore, previous characteristic epidemiologic patterns of hepatitis have undergone alterations which can be ascribed to the influx of the drug-using population. These are: Ca) the loss of the previously recognized seasonality of reported cases; (b) a change in the preponderance of hepatitis from rural to urban areas; Cc) the change from the previously noted equal frequency of the disease in both sexes to a predominance in males; and (d) a striking change in the age distribution. 22 In 1966 the majority of cases reported as viral B hepatitis involved adults over the age of 30. However, in 1972,80 per cent of cases were reported to be in individuals 15 to 24 years of age. Furthermore, in 1966, posttransfusion hepatitis constituted 55 per cent of the cases reported as hepatitis B, while in 1972, 70 per cent of cases reported as hepatitis B occurred in acknowledged parenteral drug abusers.9 This represents a change from a transfusion-associated disease of older adults in 1966, to a parenteral drug-associated disease of young adults in 1972. Parallel changes also have been noted in Veterans Administration hospitals. Patients with a diagnosis of viral hepatitis increased from a figure of 14.4 per 10,000 in 1965, of whom only 2.2 per cent were 18 to 25 years of age, to 49.1 per 10,000 discharges in 1972,60.9 per cent of whom were in this age group.59 In one VA hospital (Boston, Massachusetts) acknowledged drug abusers constituted only 5 per cent of the hepatitis cases admitted between 1963 and 1967, but 60 per cent of patients admitted with viral hepatitis between 1968 and 1971.62 Impact of Nonparenteral Transmission Until recently, it had been assumed that hepatitis was spread from one addict to another almost exclusively through the sharing of contaminated equipment. In 1967, Krugman et a1. 47 demonstrated under experimental conditions, that MS-2 (viral B) hepatitis could be transmitted orally, and further, that it was mildly contagious to close contacts. Sup-
HEPATITIS IN THE DRUG ABUSER
845
porting evidence for nonparenteral transmission of viral B hepatitis has come from numerous subsequent clinical, serologic and epidemiologic surveys.8, 11, 30, 34, 38, 48, 75 For example, cases of "sporadic" hepatitis (hepatitis without obvious parenteral exposure) have a high incidence (± 50 per cent) of HBsAg. Also, the antigen is almost endemic in certain parts of the world and in institutions for the mentally retarded, under circumstances in which overt parenteral exposure cannot be recognized. Further, it has been noted that close contacts of carriers of HBsAg develop HBsAg, antiHBs or overt hepatitis at a significantly higher rate than contacts of HBsAg-negative controls. The precise mode of transmission is unclear, although it has been speculated that certain body fluids and secretions may be responsible for transmitting the disease. Indeed, the antigen has been demonstrated in saliva and semen,27 feces,25 urine and tears,71 vaginal secretions,15 breast milk,6 and other body fluids. The infectivity of these body fluids, however, is yet to be satisfactorily demonstrated. However, spread through intimate sexual contact now seems likely, supporting the possibility that saliva or semen may well behave as vehicles for transmission. Finally, it has been suggested that airborne transmission of viral B hepatitis may occur,1 and that mosquitoes and other arthropods may act as vectors for the disease. 49
Post-transfusion Hepatitis The high risk of developing post-transfusion hepatitis after receipt of blood from commercial sources is well established.63 , 73 Commercial· blood has been shown to contain HBsAg with a frequency 12 times that of volunteer blood,12 and it is also likely that this type of blood harbors other, as yet undefined, forms of viral hepatitis. 63 Drug users have traditionally been a rich source for commercial blood procurers, and posttransfusion hepatitis has been demonstrated to follow the infusion of blood from addicts.14 In recent years, the practice of purchasing blood from these individuals has been sharply curtailed, but has by no means ceased. Indeed, 50 per cent of patients participating in the V A Cooperative Study of Liver Disease in the Drug Addict admitted to either selling or donating their blood for transfusion purposes in the recent past. 64
Risk to Medical Personnel Physicians, nurses, and technicians are at high risk of developing hepatitis through accidental inoculation while caring for patients with the disease. The growing numbers of hospitalized drug addicts with overt hepatitis, and the often unrecognized HBsAg carrier state of addicts hospitalized for other reasons, increase the risk. Indeed, almost 10 per cent of individuals who have entered a V A cooperative study of "needlestick" hepatitis (designed to evaluate the preventive effect of hepatitis B immune serum globulin) had been exposed to blood from drug addicts. 65
EFFECT ON THE DRUG USER The drug user is a hazard both to the community, and to his fellow addict. The high carrier rate of HBsAg and the high incidence of asymptomatic acute disease, makes every needle-sharing experience, even
846
LEONARD
B.
SEEFF
with apparently normal individuals, a potential episode for transmission of the disease.
Hepatitis While viral hepatitis is the most frequent infectious complication of parenteral drug abuse, it is asymptomatic and anicteric more frequently than overt. The frequency and severity of hepatitis, and the frequency of antigenemia have been reported to be higher in white than in black addicts,76 presumably the result of a greater immunity in members of lower socioeconomic groups than in those from a more affluent background. The onset of illness is usually insidious, and is preceded in almost 25 per cent of patients by a serum-sickness-like syndrome (urticaria, arthralgia, arthritis, angioneurotic edema), considered a result of HBsAg/antiHBs immune complexes.2o Acute hepatitis in the drug addict differs in several respects from that seen in other settings. These include (a) a propensity for multiple bouts; (b) the almost exclusive presence of a specific subtype; (c) certain unusual histologic features; and (d) a significant incidence of progression from acute to chronic hepatitis. Several investigators have reported that multiple episodes of apparent acute hepatitis (as many as 5 separate bouts) occur in 10 to 30 per cent of drug addicts. 26 . 38. 42. 65 Available data42 suggest that only one of these multiple bouts is associated with the HBsAg, permitting the inference that the others are the result of more than one immunologically distinct virus. That some of the bouts may be caused by the hepatitis A virus has been considered to be supported by the finding of high IgM levels in HBsAg-negative hepatitis. 38 Other, presently undefined agents (? virus C), also are suspected. However, distinction of individual bouts of acute hepatitis from reexacerbations of the original illness, may be exceedingly difficult. Documented prolonged periods of normal transaminase values between each apparent acute bout should be a minimal requirement, since it is common for drug addicts to have prolonged fluctuating transaminase abnormalities with histologic features of chronic hepatitis. In the United States, the ay subtype predominates in blood donors who are carriers of the HBsAg,18 while the subtypes ad and ay occur with approximately equal frequency in patients with acute hepatitis. 32 However, drug addicts who develop acute viral B hepatitis have HBsAg of almost exclusively the ay subtype. 24 • 55. 75 This uniformity is thought to result from continued propagation of this single subtype because of the communal living arrangements of some addicts, as well as from the regular sharing of contaminated equipment. The histology of acute hepatitis in the drug user is variable. It ranges from the typical changes of acute hepatitis (lobular disarray, ballooning degeneration, hepatocellular necrosis, acidophilic bodies, widespread inflammation) to quite mild abnormalities (scattered focal necrosis a!ld inflammation). Of particular importance is the fact that drug addicts may demonstrate the clinical and biochemical features of acute hepatitis, with histologic abnormalities strongly suggestive of chronic hepatitis (portal fibrosis, "piecemeal" necrosis, abundant plasma cells). Widening of the portal area and portal fibrosis, with occasional tongue-like projections
HEPATITIS IN THE DRUG ABUSER
847
extending into the parenchyma, is a common finding.35 This presumably represents evidence of previous, often undetected disease. Also common is the evidence of a distorted "limiting plate" and "piecemeal necrosis," a lesion generally considered indicative of chronic active hepatitis. 16 Portal inflammation may be flamboyant, consisting of "round cells," plasma cells and eosinophilic leukocytes. The profusion of plasma cells also may be of concern, because of their association with chronic liver disease. Possible explanations for their abundant presence include the suggestion that they might reflect an exacerbation of a previous acute episode of hepatitis, that they represent an inflammatory response modified by previous bouts of hepatitis from which the individual has recovered, or that they appear in response to long-continued exposure to narcotic drugs or contaminants. Despite the appearance of these disturbing features, the majority of drug addicts with acute hepatitis seem to recover without obvious chronic sequelae. Nevertheless, exaggerated evidence of these abnormalities should signal the need for careful long-term follow-up to include a repeat liver biopsy in the evaluation process. A histologic feature of particular interest to us is the· high frequency, and often the great density, of eosinophilic leukocytes in the portal areas in drug associated acute hepatitis.35 Indeed, eosinophils may be present in sufficient numbers to warrant the consideration of a hypersensitivity drug reaction or even of a parasitic infection. It has been suggested that the narcotic drugs or their contaminants may be responsible for this apparent hypersensitivity response. 29 Another, pathognomonic histologic finding in the drug abuser, is the presence of adventitious material (talc, silica, calcite) in portal macrophage and Kupffer cells.36 When sought with a polarizing lens, these particles may be found in 20 to 30 per cent of biopsies in drug addicts. An important concern is the possible development of chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH), or even of cirrhosis, in asymptomatic drug addicts who mayor may not have biochemical evidence of liver injury. Indeed, 25 per cent of the drug abusers participating in the V A Study 64 biopsied because of persistently abnormal transaminase values, have demonstrated the histologic characteristics of CAH or cirrhosis. Furthermore, data from this study have indicated that CPH and CAH, as diagnosed histologically, could not be distinguished from one another on the basis of clinical or biochemical findings. With the exception of a significantly higher incidence of the HBsAg in those with chronic active hepatitis, other biochemical tests, including serum transaminases, proteins, protein electrophoresis, and immunoglobulins, were found to be similar in the two groups. It is our belief that every drug abuser with persistently abnormal transaminase values (> 3 months), particularly when accompanied by a positive test for the HBsAg, should have a liver biopsy performed. Accurate estimation of the incidence of chronic liver disease as a sequel to acute hepatitis occurring in the drug addict awaits prospective studies. Current data suggest that approximately 12 per cent of patients with acute type B hepatitis develop CPH. Less than one third remain HBsAg positive. Approximately 1 per cent develop chronic active hepatitis and/or cirrhosis. Almost all of this group continue to be positive for HBsAg.57 A high rate of chronicity also may be inferred from studies con-
848
LEONARD
B.
SEEFF
ducted in asymptomatic drug abuse patients. Over 75 per cent of approximately 300 totally asymptomatic drug users participating in the VA drug abuse hepatitis study&' were found to have abnormal SGPT values, 9 per cent were positive for HBsAg, and 87 per cent were positive for antiHBs. Only 5 per cent had no evidence of present or past liver disease. As already noted, 25 per cent of the patients subjected to liver biopsy demonstrated histologic evidence of CAH or cirrhosis. It therefore seems evident that a high proportion of drug addicts have undetected serious chronic liver disease, which may not emerge clinically until many years later. Nonhepatic Disease Drug abusers are prone to develop a number of nonhepatic HBsAgrelated complications, presumably a result of immune complex (HBsAg/antiHBs) formation and deposition. Renal disease (membranoproliferative glomerulonephritis, focal glomerulonephritis, epimembranous glomerulonephritis) with demonstrated deposition of HBsAg, IgM and {3 1C, and which manifests as the nephrotic syndrome, has been reported.44 • 45 Polyarteritis23 and necrotizing angiitis, primarily in metamphetamine users,t3 also have been described. Arthralgias and arthritis, usually occurring during the prodromal period of acute viral B hepatitis, and sometimes associated with urticaria, occurs in as many as 25 per cent of patients:20 Finally, the presence of HBsAg in some patients with primary hepatocellular carcinoma72 has led to the concern that HBV might be an oncogenic virus. To our knowledge, HBsAg-positive primary carcinoma has not been described in a drug addict patient. However, continued, long-term observations are essential before this grave complication can be excluded. CONCLUSION Drug addicts have a high incidence of acute and chronic viral hepatitis. The acute disease in this population is characterized by apparent multiple bouts, only one of which is HBsAg-positive, the presence of HBsAg of the ay subtype, often confusing histologic abnormalities, and a high rate of progression to chronic liver disease. Important chronic liver disease (chronic active hepatitis, cirrhosis) may develop without clinical or biochemical warning, indicating that a liver biopsy is necessary for diagnostic confirmation. As a result of their high incidence of overt and asymptomatic viral hepatitis, and of their high HBsAg-carrier state, drug addicts are potential hazards to their fellow abusers, as well as to the community. ACKNOWLEDGMENT
I wish to thank Dr. Hyman J. Zimmerman for his invaluable help and constructive suggestions during the course of the preparation of this manuscript. Medical Service Veterans Administration Hospital Washington, D.e. 20422
