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BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

The dramatic growth of the pharmaceutical industry over the past 50–60 years has resulted in the development and marketing of an ever-increasing number of drugs. In the United States, medical drugs, both overthe-counter and those dispensed by prescription, are widely advertised on television, in the popular press, and on the worldwide web. The result is that the general public, especially in western countries, are accustomed to hearing about drugs and have come to expect their availability for all ailments, regardless of their severities. While most conventional drugs are designed to be beneficial, they can also cause undesired adverse effects that may range from trivial to death-dealing injury. Numerous epidemiologic surveys indicate that adverse reactions from conventional drugs account for between 3% and over 8% of all hospital admissions [1–4], and are responsible for a significant number of deaths [1,5,6]. Adverse reactions can affect all organ systems including the liver, the focus of this editorial. Herbals and dietary supplements also now play an important role in the ‘‘therapeutic armamentarium.” Herbals have been utilized by indigenous peoples and certain cultures for centuries, but interest in their use among western populations is a relatively recent phenomenon, although their frequency of use is growing exponentially and is beginning to parallel and even exceed that of conventional medications. In early telephone surveys conducted in the United States, the use

There is appropriate concern about the potential risk for hepatotoxicity from herbal products because they are unregulated and therefore not standardized with regard to their contents. This is particularly the case for the crude herbals that are commonly formulated as a mixture, so that their ingredients may be ambiguous and even contain harmful contaminants. Presented here is an overview of the more commonly recognized herbal products that have been reported to be associated with liver injury. Although many of them are clearly implicated, there are some, particularly those identified solely through an occasional case report, for which the relationship is uncertain.

Background & Aims: Studies on hepatitis C virus (HCV) quasispecies dynamics in the natural course of infection are rare owing to difficulties in obtaining samples from the early phase of infection. Methods: We studied 15 patients from the Transfusion-Transmitted Viruses Study who seroconverted to anti-HCV after receiving infected blood. Follow-up serum samples were collected every 2–3 weeks for 6 months, at 10 months, and at 11–16 years. Viral quasispecies in the second envelope hypervariable region 1 (E2/HVR1) and 5′ untranslated region (5′UTR) were analyzed with single-strand conformation polymorphism (SSCP) and heteroduplex mobility assay (HMA). Results: Seven patients cleared infection within 7–24 weeks (mean, 14.0 wk) and 3 patients eventually became anti-HCV negative. In 6 patients with resolving hepatitis the SSCP band pattern remained stable, whereas in one patient minor changes appeared before clearance. In contrast, in all 8 patients progressing to chronicity, major changes in the E2/HVR1 quasispecies developed at 8–22 weeks (mean, 13.1 wk). Shannon entropy and medium mobility shift values derived from HMA gels remained stable in patients with resolving hepatitis but changed in those who developed chronic infection. Only 2 patients showed minor changes in 5′UTR. A decrease in E2/HVR1 complexity at the time of transmission (bottleneck) was found in 5 patients altogether. Conclusions: Changes in E2/HVR1 quasispecies 8–22 weeks after infection, likely caused by mounting immune pressure, were predictive of ensuing chronic infection, whereas stability was associated with resolution. Our study also showed that composition of HCV quasispecies may be preserved during transmission from host to host.

Paraoxonase 1 (PON) may contribute to the cardioprotective action of high-density lipoprotein (HDL) because it inhibits low-density lipoprotein (LDL) oxidation, a prerequisite for the onset of atherosclerosis. Because light drinking and heavy drinking have diametrically opposite effects on cardioprotection, we have determined the effects of ethanol dosage on rat serum PON activity and its hepatic expression. Furthermore, we have investigated PON activity and polymorphism in human light and heavy drinkers. Our results confirm that HDL-PON inhibited LDL oxidation, destroyed oxidized LDL, and inhibited its uptake by macrophages. Light ethanol feeding caused a 20% to 25% (P

Hepatitis C is both a cause and a complication of chronic renal disease. Chronic infection with hepatitis C virus (HCV) can lead to the immune complex syndromes of cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN). The pathogenetic mechanisms for these conditions have not been defined, although they are clearly caused by the chronic viral infection. Management of HCV-related cryoglobulinemia and MPGN is difficult; antiviral therapy is effective in clearing HCV infection in a proportion of patients, but these conditions can be severe and resistant to antiviral therapy. Hepatitis C also is a complicating factor among patients with end-stage renal disease and renal transplants. The source of HCV infection in these patients can be nosocomial. Screening and careful attention to infection control precautions are mandatory for dialysis units to prevent the spread of hepatitis C. Prevention of spread is particularly important in these patients because HCV infection is associated with significant worsening of survival on dialysis therapy, as well as after kidney transplantation. Furthermore, therapy for hepatitis C is problematic, only partially effective, and associated with significant side effects in this population. There are significant needs in both basic and clinical research in the pathogenesis, natural history, prevention, and therapy for hepatitis C in patients with renal disease.

The incidence of newly acquired hepatitis C infection has diminished in the United States. This decline is largely because of a decrease in cases among IDUs for reasons that are unclear and, to a lesser extent, to testing of blood donors for HCV. The virus is transmitted by blood, and such transmission now occurs primarily through injection drug use, sex with an infected partner or multiple partners, and occupational exposure. Most infections become chronic, and therefore the prevalence of HCV infections is high, with about 3 million Americans estimated, to be chronically infected. HCV is a leading cause of cirrhosis, a common cause of HCC and the leading cause of liter transplantation in the United States. The disease spectrum associated with HCV infection varies greatly. Various studies have suggested that 3% to 10% of chronically infected patients will develop cirrhosis over a 20-year period, and these patients are at risk for HCC. Persons who are older at the time of infection, patients with continuous exposure to alcohol, and those coinfected with HIV or HBV demonstrate accelerated progression to more advanced liver disease. Conversely, individuals infected at a younger age have little or no disease progression over several decades. The diagnosis of chronic hepatitis C infection often is suggested by abnormalities in ALT levels and is established by EIA followed by confirmatory determination of HCV RNA. Several sensitive and specific assays are automated partly for the purposes of detecting HCV RNA and quantifying the viral level. Although there is little correlation between viral level and disease manifestations, these assays have proven useful in identifying those patients who are more likely to benefit from treatment and, particularly, in demonstrating successful response to treatment as defined by an SVR. Liver biopsy is useful in defining baseline abnormalities of liver disease and in enabling patients and healthcare providers to reach a decision regarding antiviral therapy. Noninvasive tests do not provide the information that can be obtained through liver biopsy. Information on the genotype of the virus is important to guide treatment decisions. Genotype 1, most commonly found in the United States, is less amenable to treatment than genotypes 2 or 3. Therefore, clinical trials of antiviral therapies require genotyping information for appropriate stratification of subjects. Recent therapeutic trials in defined, selected populations have shown clearly that combinations of interferons and ribavirin are more effective than monotherapy. Moreover, trials using pegylated interferons have yielded improved SVR rates with similar toxicity profiles. Results continue to show, however, that the SVR rate is less common in patients with genotype 1 infections, higher HCV RNA levels, or more advanced stages of fibrosis. Genotype 1 infections require therapy for 48 weeks, whereas shorter treatment is feasible in genotype 2 and 3 infections. In genotype 1, the lack of an early virologic response (< 2 log decrease in HCV RNA) is associated with failure to achieve an SVR. The SVR is lower in patients with advanced liver disease than in patients without cirrhosis. Ongoing trials are exploring the usefulness of combination therapy in various populations. Preliminary experience in IDUs, individuals coinfected with HIV, children, and other special groups suggests similar responses are achievable in these populations. Patients with acute hepatitis C may be treated, but specific recommendations for antiviral treatment must await further evaluation of the rate of spontaneous clearance of the virus and determination of the optimal time to initiate treatment. Preventive measures beyond blood-banking practices include prompt identification of infected individuals, awareness of the potential for perinatal transmission, implementation of safe injection practices, linkage of drug users to drug treatment programs. and implementation of community-based education and support programs to modify risk behavior. Some of these measures have been implemented successfully in the control of HIV infections, and it stands to reason that they would be valuable for reducing HCV transmission. Future advances in the diagnosis and management of hepatitis C require continued vigilance concerning the transmission of this infection, extending treatment to populations not evaluated previously in treatment trials, and the introduction of more effective therapies.

We have previously shown that chronic alcohol consumption leads to inhibition of sialylation of apolipoprotein E (apo E) that results in its impaired binding to high-density lipoprotein (HDL) molecule. Because apo E plays a major role in reverse cholesterol transport (RCT), we speculated that ethanol-mediated formation of HDL molecules without apo E may affect the RCT process. Therefore, we have investigated whether the RCT function of HDL is affected in chronic alcoholics with or without liver disease compared with nondrinkers. HDL was isolated from fasting plasma of normal subjects, n = 9 (nondrinkers), chronic alcoholics, n = 8 (ALC), and chronic alcoholics with liver disease, n = 6 (ALD). A portion of HDL sample from each subject was evaluated for its cholesterol efflux capacity from [3H]cholesterol oleate preloaded mouse macrophages. The remaining portion of each HDL sample was labeled with [3H]cholesterol oleate and evaluated for its ability to deliver cholesterol to the liver using HepG2 cells in culture. Cholesterol efflux capacity of HDLs was decreased by 83% (P < .0002) in alcoholics without liver disease and by 84% (P < .0006) in alcoholics with liver disease compared with the HDLs from nondrinkers. The capacities of HDLs to deliver cholesterol to the liver were decreased by 54% (P < .005) in alcoholics without liver disease and by 64% (P < .005) in alcoholics with liver disease compared with the HDLs from nondrinkers. The fact that further complications by liver disease in alcoholic subjects did not significantly exacerbate the extent of impairment in RCT function of HDL suggest that alcohol per se is responsible for its deleterious effects on RCT. Significantly, plasma HDL apo E concentration relative to that of apo A1 (apo E/apo A1 ratio) was also decreased by 31% to 32% (P < .0005) in alcoholics without or with liver disease compared with nondrinkers. It is therefore concluded that chronic alcohol consumption adversely affects the RCT function of HDL by altering its association with apo E due to ethanol-induced desialylation of apo E.

Over the past half-century, major strides have been made in the understanding of disease susceptibility, pathogenesis, and therapy. As a result, many new drugs have either replaced or been added to the vast array of existing medications available for the treatment of disease. Because the liver is the primary site of metabolism and biotransformation, it is not surprising that drug-induced hepatic injury is relatively common. Indeed, it has long been known that a number of widely used and generally well-tolerated drugs can cause acute liver injury. Chronic drug-induced liver disease (injury lasting more than 3 months), by contrast, was first described in the 1950s with the identification of a prolonged cholestatic illness related to chlorapromazine use. 70 Since that time, several other drugs have been implicated in the cause of chronic hepatic injury. Efforts to accurately define the frequency and spectrum of drug-induced chronic liver disease faces several obstacles. On the one hand, many drugs may cause clinically inapparent liver injury. As a consequence, estimates of the true incidence of drug-induced liver disease may be falsely low. On the other hand, case reports in the literature tend to focus on the most severe or fatal drug-related reactions, creating the impression of a falsely elevated drug-associated morbidity and mortality. Lastly, the potential for drugs to cause liver injury must take into account the intrinsic or predictable ability of the drug to produce injury (e.g., via toxins) as well as host susceptibility factors that may lead to unpredictable injury. Taking these factors into account, recent data suggest that drug-induced liver injury occurs in approximately 1 in 600 to 1 in 3500 hospital admissions. 28 Two percent to 5% of hospital admissions for jaundice in the United States are drug-induced, as are between 15% to 30% of instances of fulminant hepatic failure, and 20% to 50% of cases of nonviral chronic hepatitis. 26,28,41,55 At present, 500 to 1000 agents have been implicated in the cause of a broad spectrum of liver diseases. 32,103,120

Within a short time of the recognition of acute non-A, non-B (NANB) hepatitis, identified in the course of enzyme-monitored transfusion studies conducted during the early 1970s, it became clear that, despite a paucity of symptoms, the illness failed to resolve in approximately half of those affected. The evidence for disease persistence was the fact that the serum enzymes, specifically alanine aminotransferase (ALT), continued to remain abnormal for periods in excess of 6 months. Now labeled chronic hepatitis by convention, liver biopsy examination confirmed this clinical diagnosis through the identification of histologically-defined chronic hepatitis of graded severity in about 50% to 60% of instances and of cirrhosis in another 20%. Despite these findings, most affected persons remained oblivious to these outcomes because of continued lack of symptoms. The detection almost a decade and a half later of the hepatitis C virus (HCV) provided a further tool for identifying chronicity. With the development of the highly sensitive polymerase chain reaction (PCR), it was possible to identify the persistence of HCV RNA in an additional group, even in the absence of raised ALT values. Currently, it is believed that approximately 85% of acutely infected individuals fail to recover fully following acute HCV infection. Short-term prospective, point-prevalence, and retrospective studies have since shown that, once chronically infected with HCV, such persons are at risk of progressing from histologically defined chronic hepatitis to cirrhosis and, in some instances, to hepatocellular carcinoma (HCC). More often than not, these events can continue to occur in the complete absence of symptoms which may emerge only when end-stage liver disease is reached. The true frequency and rate of these progressive changes have represented an area of uncertainty and have led to conflicting views on the subject. Some authorities have suggested that progression to severe end-stage liver disease is inevitable, provided the infected person does not succumb first to another lethal illness; others have concluded that disease progression is restricted to a limited few and that the challenge is to define factors that might account for wide differences in outcome. These opposing views can be accounted for, at least in part, by the extraordinarily insidious nature of the process and the almost snails' pace rate of its progression. Efforts to resolve this controversy are required for two obvious reasons: (1) the need to inform HCV carriers of what to anticipate in their future in the hope of reassuring them about potential sequelae; and (2) the need to make prudent decisions regarding therapy with drugs that are currently of only limited therapeutic benefit. The only means of resolving the conflict is to conduct appropriate long-term studies of the natural history of the disease.

Nearly all analgesic and anti-inflammatory agents have the potential for hepatic injury. Most nonsteroidal anti-inflammatory drugs (NSAIDs) produce injury in an unpredictable fashion by way of an idiosyncratic (immunologic versus metabolic) mechanism, whereas acetaminophen and aspirin are more predictable because they produce injury in a dose-dependent manner by way of intrinsic toxicity. Both acetaminophen and aspirin may produce hepatotoxicity despite therapeutic intent. This article discusses specific NSAIDs available in the United States and abroad and their associated hepatotoxicity and carefully considers acetaminophen-related hepatotoxicity reviewing risk factors for injury, clinical features, prognosis, and management.

Our hypothesis is that because of its hepatic metabolism paraaminobenzoic acid (PABA) could be a test of liver function. PABa is well absorbed by the gastrointestinal tract and acetylated and conjugated in the liver to glycine before being excreted. Its three major metabolites include para-acetoamidobenzoic acid (PAABA), paraaminohippuric acid (PAHA), and paraacetamidohippuric acid (PAAHA). In this study, we measured the metabolism of lidocaine to monoethylglycinexylidide (MEGX) and PABA to PAHA + PAAHA/PABA + PAABA + PAHA + PAAHA (hippurate ratio) in 14 patients with liver disease and 12 control subjects. Comparison of the total bilirubin with the hippurate ratio (at 30 min) and the conventional MEGX test (at 15 min) was assessed. The 30 min hippurate ratio correlated well with the 15 min MEGX results (r = 0.69). While these results are preliminary the PABA test appears to be equally sensitive to MEGX and has the distinct advantage over the MEGX test of being administered orally versus the intravenous administration of lidocaine which is often associated with unwanted side-effects such as hypotension, drowsiness and paresthesias.

Jaundice during pregnancy may be the result either of disease uniquely associated with the pregnant state or disease totally unrelated to the pregnancy. In the United States, the most common cause of jaundice in pregnant women is viral hepatitis. With the exception of hepatitis E virus infection, the clinical course and histologic findings do not differ between pregnant and nonpregnant patients.

Herbal products have been used for centuries among indigenous people to treat symptoms and illnesses. Recently, their use in Western countries has grown significantly, rivaling that of prescription medications. Currently, herbal products are used mainly for weight loss and bodybuilding purposes but also to improve well-being and symptoms of chronic diseases. Many people believe that because they are natural, they must be effective and safe; however, these beliefs are erroneous. Few herbal products have been studied in well-designed controlled trials of patients with liver or other diseases, despite testimony to the contrary. Moreover, current highly effective antiviral drugs make efforts to treat hepatitis C with herbal products redundant. Herbal products are no safer than conventional drugs and have caused liver injury severe enough to require transplantation or cause death. Furthermore, their efficacy, safety, and claims are not assessed by regulatory agencies, and there is uncertainty about their reported and unreported contents. We review the history of commonly used herbal products, as well as their purported efficacies and mechanisms and their adverse effects.

Non-A, non-B hepatitis, previously transmitted to chimpanzees by inoculation of human serum, was serially transmitted through a second and third passage to additional chimpanzees using serum drawn during acute non-A, non-B hepatitis. Sera obtained at weeks 4 and 5 after inoculation from two different chimpanzees, and from one chimpanzee at week 13 after inoculation, were shown to cause elevation of serum aminotransferase levels and abnormal liver biopsies in recipient chimpanzees, with no serologic evidence of hepatitis A or B, cytomegalovirus, or Epstein-Barr virus infection. Serum obtained 3 wk after inoculation did not cause elevation of aminotransferase levels in the recipient chimpanzee, although a single abnormal biopsy was obtained. Thus, the non-A, non-B hepatitis agent was present in serum during acute disease near the time of the first aminotransferase elevation (week 4; perhaps also week 3), and persisted at least until 1 week after the peak aminotransferase level (week 13).

The concept of immunotherapy and immunoprophylaxis for infectious diseases was introduced to clinical medicine in 1890, when von Behring and Kitasato reported that they had developed an antitoxin against diphtheria." The work they performed was so highly regarded that von Behring was selected to receive the Nobel Prize for Physiology and Medicine in 1901, the first year of the award. The immunologic basis of these studies remained valid, but the antitoxin itself proved to be of only limited use. Because it was a rabbit antiserum, 'it produced frequent and often life threatening hypersensitivity reactions in humans. Immunoprophylaxis with material derived from human sources was first used in the early 1930s. Among the studies performed was one by McKhann and Chu who demonstrated that a globulin fraction, prepared by ammonium sulfate precipitation of placental extract, could attenuate and even prevent the development of measles in susceptible persons! A relevant advance in methodology came in 1936 when Tiselius reported that serum proteins could be separated and purified by electrophoresis. 3 Shortly thereafter, he and Kabat showed that the serum antibodies were concentrated in the gamma globulin fraction of the proteins.Human gamma globulin concentrated by this method was also found to be effective for the prophylaxis of measles. ,6 Furthermore, because the globulin was derived from human sources, the problem of hypersensitivity was, found to be far less prevalent than had been noted with the heterologous antitoxins. Before the wide-scale use of gamma globulin

Fifty lots of immune serum globulin prepared by four United States manufacturers between 1944 and 1977 were tested for the presence and titer of antibody to the hepatitis B virus-associated δ-agent. Anti-δ was detected in 28 of the 50 lots (56%) of immune serum globulin at titers ranging from 1:10 to 1:400. Anti-δ was present in 75% (6 of 8) of lots produced between 1962 and 1965, in 77% (17 of 21) produced between 1967 and 1970, in 45% (5 of 11) produced between 1971 and 1972 and in none (0 of 9) produced since 1973. A single lot of globulin prepared from plasma that was collected in 1944 from United States Army soldiers also contained detectable anti-δ. These data indicate that δ-infection has been occurring among hepatitis B surface antigen (HBsAg) carriers in the United States since the 1940s. The decrease in prevalence of anti-δ in immune serum globulin lots coincided with the start of routine HBsAg screening of blood and plasma. The elimination of HBsAg-positive units from plasma pools has reduced levels of HBsAg and anti-δ and should have decreased the risk of transmission of both type B hepatitis and δ-hepatitis by plasma products.

Systemic and extrahepatic infectious disease can lead to biochemical changes indicative of hepatic involvement and even to jaundice.lm3 For the most part the hepatic involvement is overlooked or recognized as an inconsequential component of an identified systemic illness. Furthermore, in the case of viral infections, misconstruing the illness as hepatic rather than systemic would not affect therapy significantly. Bacterial infection as a cause of jaundice, however, if overlooked would fail to receive appropriate therapy.’ Indeed, this appears to be particularly relevant to gram-negative bacterial infections, which are recognized by pediatricians to be an important cause of jaundice in infants.4-‘2 The icterogenie role of infections due to gram-negative bacteria in adults,2.3.‘3-‘7 which is much less appreciated, is illustrated by a patient to be described by Dr. Fang.

A double blind, randomized, controlled trial has been conducted in 11 Veterans Administration hospitals during a 49-month period to compare the relative efficacies of immune serum globulin (ISG) and an albumin placebo for the prevention of post-transfusion hepatitis (PTH). A total of 2204 patients, of whom 1094 received ISG, participated in the study. The results indicate that ISG significantly reduced the incidence of icteric type non-B hepatitis only (inferred to be also type non-A hepatitis). Adverse reactions were rare, and the ISG did not significantly alter the incubation period or duration of the disease. The data suggest, however, that a similar reduction in type non-A, non-B hepatitis would have occurred had commercial blood been excluded from use. Analysis of the 241 patients who developed hepatitis indicates that type B hepatitis constituted less than 20% of the cases each year of the study. Furthermore, the efficacy of the ISG, manufactured in 1944, against apparent type non-A, non-B hepatitis suggests that this overlooked disease has existed from at least that time. Host- and transfusion-related factors that might have modified the development of PTH were examined. The use of commerical blood was observed to be the most important risk factor. It is concluded that the PTH incidence can be most effectively reduced by eliminating commercial donor blood, and continuing to screen volunteer donors for hepatitis B surface antigen (HBsAg) by sensitive procedures. Of prime importance is the need to define the agent(s) responsible for type non-A, non-B hepatitis.

The significance of megamitochondria in the alcoholic liver injury of humans was investigated as part of a large Veterans Administration cooperative study of the natural history of alcoholic hepatitis. Two hundred twenty patients were clinically stratified into the following three groups according to disease severity using serum bilirubin and prothrombin time as indicators: Group 1 (mild disease), serum bilirubin levels less than 5 mg/dl and prothrombin time prolonged for less than 4 s; group 2 (moderate disease), serum bilirubin levels greater than 5 mg/dl but prothrombin time prolonged for less than 4 s; and group 3 (severe disease), serum bilirubin levels greater than 5 mg/dl and prothrombin time prolonged for greater than 4 s. Megamitochondria were observed in 20% of the patients (45 of 220). Of these, 43 patients were in groups 1 and 2 of severity and only 1 patient belonged in group 3. The association of megamitochondria with cirrhosis was infrequent (33%, 15 of 45 patients). The differences in severity correlated with the differences in mortality: in patients with megamitochondria, only 1 had died at 6 mo compared with 40 deaths in patients without megamitochondria. By 12 mo, there were two deaths in patients with megamitochondria versus 51 deaths in those patients without. No complications were present in 72% of patients with megamitochondria versus 39% for those without. Infection, gastrointestinal bleeding, pancreatitis, hyperglycemia, azotemia, delirium tremens, seizures, and hepatic encephalopathy were all more common in patients without megamitochondria. The patients with megamitochondria appear to represent a subcategory of alcoholic hepatitis with a milder degree of clinical severity, lower incidence of cirrhosis, fewer complications, and good long-term survival.

Among 37 patients with hepatocellular carcinoma given systemic chemotherapy, 12 (32 percent) lived 14 to 37 months from initiation of treatment whereas the remainder died within five months. Individual factors associated with improved survival included fully ambulatory performance status, lack of jaundice, response to chemotherapy, the fibrolamellar carcinoma pathologic variant, absence of cirrhosis, and normal serum alpha-fetoprotein levels. Patients living longer than 12 months fell into two groups. Seven patients with fibrolamellar carcinoma lacked evidence of hepatitis B serum markers or cirrhosis and had normal alpha-fetoprotein levels and surprisingly frequent extrahepatic metastases. All but one were Caucasians aged 25 years or less. The other five "long-term" survivors were all fully ambulatory without jaundice, and the majority were older non-Caucasians with tumor confined to the liver at the time of diagnosis and with hepatitis B markers, elevated alpha-fetoprotein levels, or cirrhosis. All patients without fibrolamellar carcinoma who were less than fully ambulatory or who had jaundice died quickly. Patients with fibrolamellar carcinoma have homogeneous clinical features, and their disease follows a relatively indolent course. In other patients with hepatocellular carcinoma, assessment of ambulatory status and serum bilirubin determination can identify those with some prospect of prolonged survival.

A case is described of presumed quinidine hepatotoxicity, characterized by thedevelopment of fever, abnormal serum transaminase values, which improved after cessation of the drug but recurred after a challenge dose, and centrizonal hepatocellular necrosis detected on liver biopsy. Morphological changes on electron microscopy, consistent with a drug reaction, are also described. Pertinent features of previous case reports are analyzed, and the histological findings by light microscopy of the present and past cases are discussed. It is suggested that the development of unexplained fever within 1 month of quinidine administration should lead to consideration of possible hepatotoxicity.

The acute effect of chlorpromazine on the function of the perfused rat liver was evaluated by monitoring the removal of sulfobromophthalein (BSP) from the perfusate, the biliary excretion of the dye and the rate of bile and perfusate flow. The higher drug concentrations used, 2.5 × 10 −4 , 5 × 10 −4 and 10 −3 M l . of perfusate, led to a decreased rate of removal of BSP from the perfusate and of biliary excretion of the dye, accompanied by a significant reduction of perfusate flow and bile production. These changes were porportional to the concentration of the drug. The lowest dose used, 10−4 M l ., resulted in similar but more transient effects. In accord with other related studies, it is suggested that chlorpromazine may have an intrinsic toxic effect on the liver.