Lidija M. Petrovic

Acute hepatitis associated with the Chinese herbal product Jin Bu Huan

Estimates of the percentage of patients using alternative medications worldwide range from 4% to 50% [1]. According to a recent U.S. survey, 34% of adult respondents used unconventional therapy and 3% used herbal medicines [2]. In 1990, Americans made 425 million visits to providers of unconventional therapy, which exceeded the number of visits to all primary care physicians, and they spent

Expression of HGF, Its Receptor c-met, c-myc, and Albumin in Cirrhotic and Neoplastic Human Liver Tissue

13.7 billion, which exceeded the cost of all hospitalizations in the United States [2]. Herbal products are rapidly gaining popularity in North America as remedies for various medical conditions. Jin Bu Huan Anodyne Tablets (Lycopodium serratum), a traditional Chinese herbal remedy, has been used for more than 1000 years as a sedative and analgesic but has only been available in the United States for 10 years [3]. The alkaloid levo-tetrahydropalmatine is responsible for the morphine-like properties of Jin Bu Huan [4]. A recent study [5] described three children who had taken unintentional overdoses of Jin Bu Huan tablets and who developed central nervous system and respiratory depression with bradycardia. We subsequently identified three adult patients with acute hepatitis associated with Jin Bu Huan ingestion and reported this information to the Centers for Disease Control and Prevention and to the Food and Drug Administration [6]. In the present report, we describe the clinical and laboratory features of seven adult patients (including the previously described patients) who ingested Jin Bu Huan and discuss possible mechanisms for Jin Bu Huan hepatotoxicity. Methods Patients All seven patients were white and had no history of hepatic disease, obesity, diabetes mellitus, or atopy. Six of seven patients were women. All denied a history of excessive alcohol or hepatotoxic drug intake. Risk factors for viral hepatitis were absent in all patients. Five patients resided in Los Angeles, California; three patients had purchased Jin Bu Huan Anodyne Tablets (Kwangsi Pai Se Pharmaceutical/Bose Drug Manufactory, Kwangsi, China) at the same drug store. Two other patients resided in Hawaii and Toronto, Canada, respectively. All patients developed symptoms between March 1993 and March 1994 with the exception of patient 7, whose symptoms began in 1991. Ultrasound examinations of the liver and biliary tract were normal in each patient. Serologic test results in all seven patients were negative for antinuclear, anti-smooth muscle, and antimitochondrial antibodies. Prothrombin times were normal throughout the course of illness of each patient. Case Reports Patient 1 A 66-year-old woman presented to her physician with symptoms of fever, nausea, and fatigue for 5 weeks. She was anicteric with a palpable, nontender liver. Stigmata indicating chronic liver disease were absent. She had taken 2 tablets of Jin Bu Huan at night, 2 to 3 times a week for the previous 3 months, for back pain and insomnia. Her medical history included osteoarthritis. She had used nonsteroidal anti-inflammatory drugs during the previous 2 years without adverse effects. Results of serologic tests showed convalescent antibodies for viral hepatitis A and B. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was negative. Table 1. Liver Test Results in Patients with Jin Bu Huan Toxicity* Two weeks after she stopped taking Jin Bu Huan, maximal levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were 9.4 kat/L and 5.2 kat/L, respectively, and were near normal 3 weeks later Table 1 and Figure 1 A. At this time, the patient resumed use of Jin Bu Huan for insomnia (2 tablets each night for 7 days). Two weeks after she resumed taking Jin Bu Huan, symptoms returned and enzyme levels were again increased (ALT, 16.0 kat/L; AST, 9.9 kat/L). Liver test results returned to normal 3 weeks later. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was repeated, and the result was again negative. Twelve weeks later, she was asymptomatic and liver test results were normal. Figure 1. Effect of Jin Bu Huan Anodyne Tablets on aminotransferase levels. Patient 2 A 24-year-old woman presented to her physician with symptoms of fever, nausea, vomiting, fatigue, and pruritus for 3 weeks. She had deep jaundice, excoriations of her extremities, and tender hepatomegaly. Stigmata indicating chronic liver disease were absent. She was hospitalized for 5 days. She had taken 4 tablets of Jin Bu Huan at night for insomnia, 4 times a week for the previous 2 months. She stopped taking Jin Bu Huan 1 week after the onset of symptoms. She had used an oral contraceptive pill daily for the previous 8 years. No other medical illness was present. In-hospital results of liver tests showed the following maximal levels: ALT, 24.5 kat/L; AST, 14.9 kat/L; alkaline phosphatase, 2.2 kat/L; and total bilirubin, 479 mol/L. Results from ultrasound examination of the liver and biliary tract were normal. Results of serologic tests for viral hepatitis A, B, and C; cytomegalovirus; and Epstein-Barr virus were negative. The level of serum ceruloplasmin was normal. The peripheral leukocyte count increased to 10.8 109/L with 7% eosinophils (normal, <3% eosinophils). The liver biopsy specimen showed acute hepatitis with focal necrosis, cholestasis, and inflammation with numerous eosinophils in the portal tracts, results consistent with a drug reaction (Figure 2). Pruritus improved with cholestyramine treatment. Nine weeks after discontinuing Jin Bu Huan use, she was asymptomatic and anicteric, showed resolution of eosinophilia, and had normal liver test results (Table 1). Figure 2. Liver biopsy specimen from patient 2. arrow arrows arrows arrows Patient 3 A 45-year-old woman, a friend of patient 2, presented to her physician with symptoms of nausea, anorexia, fatigue, pruritus, and right upper quadrant abdominal pain. Physical examination showed tender hepatomegaly. Stigmata indicating chronic liver disease were absent. She had taken 4 tablets of Jin Bu Huan at night for insomnia, 3 to 4 times a week for the previous 12 weeks. During the previous 6 months, she had intermittently used another Chinese herbal product, Ma Huang (active ingredients are ephedrine and pseudoephedrine), without adverse effects. She had used no other medications and had no medical illness. She stopped taking both herbal products because of her illness. Two weeks later, she noted jaundice. Results from liver tests showed the following maximal levels: ALT, 21.8 kat/L; AST, 16.7 kat/L; alkaline phosphatase, 3.8 kat/L; and total bilirubin, 58 mol/L. Results of serologic tests for viral hepatitis A, B, and C and Epstein-Barr virus were negative. During the next 4 weeks, symptoms resolved and liver tests showed decreased levels of enzymes (Table 1). However, 12 weeks after she stopped taking the herbal product, she developed an unidentified illness and increased aminotransferase levels. She denied using Jin Bu Huan, alcohol, or other hepatotoxic drugs. Tests for viral hepatitis A, B, and C and Epstein-Barr virus were repeated, and the results were negative for these viruses. Results from liver tests were maximal 7 weeks later (ALT, 10.2 kat/L; AST, 6.5 kat/L) and were normal by 19 weeks (a total of 30 weeks after cessation of Jin Bu Huan). Patient 4 A 48-year-old woman residing in Hawaii presented to her physician with fatigue and a temperature of 40.6 C. The physical examination was normal, and stigmata indicating chronic liver disease were absent. She had taken 3 tablets of Jin Bu Huan nightly for 7 weeks for insomnia. She had used no other medications and had no other medical illness. Liver test results were abnormal (ALT, 3.2 kat/L; AST, 1.2 kat/L; and alkaline phosphatase, 9.2 kat/L). Results of serologic tests for viral hepatitis A, B, and C and Epstein-Barr virus were negative, and the serum ceruloplasmin level was normal. The peripheral leukocyte count was 9.3 109/L with 6% eosinophils. After cessation of Jin Bu Huan, she became asymptomatic, her eosinophilia resolved, and liver test results returned to normal within 4 weeks (Table 1). Patient 5 A 46-year-old man presented to his physician with a temperature of 40.6 C, headaches, fatigue, and tender hepatomegaly. Stigmata indicating chronic liver disease were absent. He had taken 3 tablets of Jin Bu Huan for insomnia, 3 times a week intermittently for 6 months. He had used no other medications and had no other medical illness. Aminotransferase levels were abnormal 2 weeks after stopping Jin Bu Huan (ALT, 6.7 kat/L; AST, 4.7 kat/L). Results of serologic tests for viral hepatitis A, B, and C were negative, and the serum ceruloplasmin level was normal. Five weeks after he stopped taking Jin Bu Huan, symptoms improved and liver test results were normal Table 1 and Figure 1 B. After reuse of Jin Bu Huan for 4 weeks, the ALT level increased to 1.7 kat/L. A second-generation enzyme-linked immunosorbent assay for anti-hepatitis C virus was negative. After Jin Bu Huan use was discontinued, liver test results returned to normal in 4 weeks. Patient 6 A 31-year-old woman presented to her physician with nausea, vomiting, malaise, and deep jaundice. The physical examination was normal, and stigmata indicating chronic liver disease were absent. She had taken 6 tablets of Jin Bu Huan for insomnia, 4 to 6 times a week intermittently for 10 months and then nightly for 8 weeks. She had used no other medications and had no other medical illness. Liver test results were abnormal (ALT, 35.8 kat/L; AST, 17.4 kat/L; alkaline phosphatase, 2.8 kat/L; and total bilirubin, 262 mol/L). Results of serologic tests for viral hepatitis A, B, and C were negative, and the serum ceruloplasmin level was normal. Two weeks after she stopped taking Jin Bu Huan, liver test results showed that the enzyme levels were decreasing (Table 1). She is presently asymptomatic. Patient 7 A 53-year old woman residing in Toronto, Canada, presented to her physician with

Acute liver failure due to lymphoma

Hepatocellular carcinoma (HCC) is a common type of cancer, with approximately 260,000 new cases each year, and liver cirrhosis is generally considered a major predisposing factor for HCC. However, specific changes of gene expression in liver cirrhosis and HCC remain obscure. The expression of genes for hepatocyte growth factor (HGF), its receptor c-met proto-oncogene, c-myc proto-oncogene, and albumin was analyzed. Gene expression was studied by PCR in seven normal human livers, nine cases of hepatitis C cirrhosis, 12 cases of alcoholic cirrhosis, two cases of liver adenoma, and 12 cases of HCC. HGF and c-met protein were revealed by immunofluorescent staining. HGF mRNA was not expressed in normal livers but was detected in adenomas, in 80% of HCC, and in some cirrhoses. Paraffin-embedded and fresh-frozen tissue samples yielded similar results. Immunohistochemical data correlated with PCR results regarding the overexpression of the HGF/c-met system in HCC. Albumin gene expression was decreased in HCC vs normal livers, consistent with altered function of tumor hepatocytes. The elevated expression of the HGF/c-met system in HCC may play a role in tumor development and/or progression. Tissue localization studies of HGF and its receptor c-met protein support the existence of both autocrine and paracrine mechanisms of action of HGF in HCC vs only a paracrine mechanism in normal liver.

Transplantation of hepatocytes for prevention of intracranial hypertension in pigs with ischemic liver failure.

Lymphomatous involvement of the liver may present as acute liver failure but is an absolute contraindication for liver transplantation. Therefore it is imperative to diagnose such patients since survival in this group is poor and recurrence is high. We describe two patients with acute liver failure referred for liver transplantation whose diagnostic testing revealed hepatic lymphoma. These cases underscore the importance of considering lymphoma in the differential diagnosis of acute liver failure prior to liver transplant.

Lack of Hepatocyte Growth Factor Receptor (c-met) Gene Expression in Fulminant Hepatic Failure Livers Before Transplantation

Intracranial hypertension leading to brain stem herniation is a major cause of death in fulminant hepatic failure (FHF). Mannitol, barbiturates, and hyperventilation have been used to treat brain swelling, but most patients are either refractory to medical management or cannot be treated because of concurrent medical problems or side effects. In this study, we examined whether allogeneic hepatocellular transplantation may prevent development of intracranial hypertension in pigs with experimentally induced liver failure. Of the two preparations tested--total hepatectomy (n = 47), and liver devascularization (n = 16)--only pigs with liver ischemia developed brain edema provided, however, that animals were maintained normothermic throughout the postoperative period. This model was then used in transplantation studies, in which six pigs received intrasplenic injection of allogeneic hepatocytes (2.5 x 10(9) cells/pig) and 3 days later acute liver failure was induced. In both models (anhepatic state, liver devascularization), pigs allowed to become hypothermic had significantly longer survival compared to those maintained normothermic. Normothermic pigs with liver ischemia had, at all time points studied, ICP greater than 20 mmHg. Pigs that received hepatocellular transplants had ICP below 15 mmHg until death; at the same time, cerebral perfusion pressure (CPP) in transplanted pigs was consistently higher than in controls (45 +/- 11 mmHg vs. 16 +/- 18 mmHg; p < 0.05). Spleens of transplanted pigs contained clusters of viable hepatocytes (hematoxylin-eosin, CAM 5.2). It was concluded that removal of the liver does not result in intracranial hypertension; hypothermia prolongs survival time in both anhepatic pigs and pigs with liver devascularization, and intrasplenic transplantation of allogeneic hepatocytes prevents development of intracranial hypertension in pigs with acute ischemic liver failure.

Hepatitis C virus is not recoverable from liver tissue in cryptogenic cirrhosis: Failure to identify hepatitis C virus-RNA using reverse transcription-mediated polymerase chain reaction

To gain insight into liver regenerationmechanisms in fulminant hepatic failure, we comparedgene expression of hepatocyte growth factor, itsreceptor c-met, c-myc, and albumin in human normal (4cases) and fulminant (14 cases) livers by reversetranscription-polymerase chain reaction. In normallivers, hepatocyte growth factor gene was not expressed,whereas c-met, c-myc and albumin genes were always expressed. In fulminant hepatic failure,hepatocyte growth factor gene was expressed in 1 of 14cases, c-met in none of 14 cases, c-myc in 10 of 14cases, and albumin in 3 of 14 cases. Byimmunofluorescence, c-met protein was revealed in normal but not infulminant hepatic failure liver tissue. Liver tissue isunlikely to account for high hepatocyte growth factorplasma levels typical for fulminant hepatic failure. Lack of its receptor (c-met)expression may explain a poor response of fulminanthepatic failure livers to exogenous hepatocyte growthfactor that normally promotes liver growth andregeneration.

Metastatic Pancreatic Adenocarcinoma to the Heart Diagnosed Antemortem

Polymerase chain reaction (PCR) has been used to study liver biopsy tissue in patients with known or suspected hepatitis C virus (HCV). Recent studies of cryptogenic cirrhosis using PCR have been based on study of sera, and HCV has not been shown. The failure to show HCV in patients so studied has left unanswered the question of whether or not patients with cryptogenic cirrhosis could still harbor the virus in the liver. The authors studied liver tissue, obtained at the time of orthopic liver transplantation from 10 patients clinically diagnosed as having end-stage liver disease without demonstrable origin, so-called cryptogenic cirrhosis, using reverse transcription (RT)-PCR to try to recover HCV-RNA. Formalin-fixed, paraffin-embedded tissue was used. For comparison, the authors also studied similarly obtained samples from 10 patients with typical hepatitis C-associated cirrhosis and 10 patients with end-stage liver disease resulting from autoimmune hepatitis. The authors recovered HCV-RNA from 9 of 10 livers from patients with cirrhosis resulting from HCV, and 3 of 10 livers from patients with autoimmune hepatitis. HCV-RNA was not recovered from any of the livers of the 10 patients designated as having cryptogenic cirrhosis.

Comparison of histopathology in acute allograft rejection and recurrent hepatitis C infection after liver transplantation

Pancreatic tumors frequently metastasize widely, though it is rare to diagnose pancreatic cardiac metastases in the antemortem state. We report an unusual case of metastatic pancreatic adenocarcinoma to the right atrium. Transesophageal echocardiography showed that the tumor was attached to the superior aspect of the right atrium, prolapsing through and obstructing the tricuspid valve in diastole and retracting back into the right atrium during systole. The tumor was excised, and histologic examination confirmed the presence of moderately differentiated adenocarcinoma with a papillary architectural pattern and with desmoplastic stroma, features comparable to the original primary pancreatic neoplasm.