Sergio Rojter

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

Simeprevir plus sofosbuvir (12 and 8 weeks) in hepatitis C virus genotype 1-infected patients without cirrhosis: OPTIMIST-1, a phase 3, randomized study.

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

Effective antiviral therapy is essential for achieving sustained virological response (SVR) in hepatitis C virus (HCV)‐infected patients. The phase 2 COSMOS study reported high SVR rates in treatment‐naive and prior null‐responder HCV genotype (GT) 1‐infected patients receiving simeprevir+sofosbuvir±ribavirin for 12 or 24 weeks. OPTIMIST‐1 (NCT02114177) was a multicenter, randomized, open‐label study assessing the efficacy and safety of 12 and 8 weeks of simeprevir+sofosbuvir in HCV GT1‐infected treatment‐naive and treatment‐experienced patients without cirrhosis. Patients were randomly assigned (1:1; stratified by HCV GT/subtype and presence or absence of NS3 Q80K polymorphism [GT1b, GT1a with Q80K, GT1a without Q80K]), prior HCV treatment history, and IL28B GT [CC, non‐CC]) to simeprevir 150 mg once daily+sofosbuvir 400 mg once daily for 12 or 8 weeks. The primary efficacy endpoint was SVR rate 12 weeks after end of treatment (SVR12). Superiority in SVR12 was assessed for simeprevir+sofosbuvir at 12 and 8 weeks versus a composite historical control SVR rate. Enrolled were 310 patients, who were randomized and received treatment (n = 155 in each arm). SVR12 with simeprevir+sofosbuvir for 12 weeks (97% [150/155; 95% confidence interval 94%‐100%]) was superior to the historical control (87%). SVR12 with simeprevir+sofosbuvir for 8 weeks (83% [128/155; 95% confidence interval 76‐89%]) was not superior to the historical control (83%). The most frequent adverse events were nausea, headache, and fatigue (12‐week arm: 15% [23/155], 14% [22/155], and 12% [19/155]; 8‐week arm: 9% [14/155], 17% [26/155], and 15% [23/155], respectively). No patients discontinued treatment due to an adverse event. One (1%, 12‐week arm) and three (2%, 8‐week arm) patients experienced a serious adverse event (all unrelated to study treatment). Conclusion: Simeprevir+sofosbuvir for 12 weeks is highly effective in the treatment of HCV GT1‐infected patients without cirrhosis, including those with Q80K. (Hepatology 2016;64:370‐380)

Analysis of clinical course and prognosis of culture-positive spontaneous bacterial peritonitis and neutrocytic ascites. Evidence of the same disease.

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.

Detection of hepatitis C virus with RNA polymerase chain reaction in fulminant hepatic failure

The clinical significance and prognosis of culture-negative neutrocytic ascites in cirrhotic patients is a controversial topic. In the present study, the clinical and humoral presentation and the short-and long-term prognosis were analyzed in 36 patients with cirrhosis and culture-positive spontaneous bacterial peritonitis and in 28 patients with cirrhosis and ascitic fluid polymorphonuclear count greater than 250/mm3, a negative ascitic fluid culture, and without previous antibiotic therapy. On admission there were no significant differences between groups related to age, sex, alcoholism, fever, abdominal pain, serum albumin, serum urea, serum creatinine, Child-Pugh score, polymorphonuclear count, and total protein concentration in ascitic fluid. A greater frequency of positive blood culture was found in patients with spontaneous bacterial peritonitis (15/21 vs 2/18) (P<0.001). Mortality during the first episode was 36% in patients with spontaneous bacterial peritonitis and 46% in patients with culture-negative neutrocytic ascites (NS). Mortality during follow-up was high and survival probability at 12 months was 32% in spontaneous bacterial peritonitis and 31% in culture-negative neutrocytic ascites. The probability of recurrence at 12 months was 33% in spontaneous bacterial peritonitis and 34% in culture-negative neutrocytic ascites. Our results show that spontaneous bacterial peritonitis and culture-negative neutrocytic ascites are variants of the same disease with a high mortality and poor prognosis.

Morbidity and mortality of recurrent hepatitis C infection after orthotopic liver transplantation

The role of hepatitis C virus (HCV) infection in fulminant hepatic failure is controversial. The frequency of serum HCV RNA positivity in previously reported patients with fulminant hepatic failure (FHF) of indeterminate cause ranged from 0 to 12% in the United States and Europe and from 43% to 59% in Asia. We assessed serum HCV RNA using polymerase chain reaction (PCR) and oligoprimers from the 5′UTR of the HCV genome in 26 consecutive patients with FHF. Another laboratory independently performed PCR on 21 of the serum samples using different oligoprimers from the 5′UTR and NS3 region of the HCV genome. Serum HCV RNA was detected in two of seven (28%) patients with hepatitis B, 9 of 15 (60%) with an indeterminate cause, and in none with hepatitis A (n = 2) or drug‐induced hepatotoxicity (n = 2). HCV RNA PCR results were concordant between both laboratories in 17 of 21 (81%) of samples. In patients with an indeterminate cause, HCV RNA positivity was significantly associated with the transmission risk factor of low socioeconomic status and Hispanic ethnicity. Eighteen patients underwent liver transplantation (LT) and 15 (83%) survived. Among patients with FHF of indeterminate cause, recurrent or acquired HCV infection after transplantation occurred in three of five (60%) and one of four (25%) patients, respectively. Three of four (75%) patients with hepatitis C virus infection post‐LT also developed histologic hepatitis. HCV appears to be the causative agent of a substantial number of cases of FHF classified as indeterminate in the Los Angeles area. Differences in patient populations or risk factors may explain the discordant incidences of HCV infection in FHF observed among different programs. (Hepatology 1995; 22:1379–1386).

Vasodilatory effects of propylthiouracil in patients with alcoholic cirrhosis

Summary. Through molecular virological testing it is now clear that HCV reinfection of the allograft is virtually universal in liver transplant recipients. Although histopathological recurrence of hepatitis C occurs in the majority of patients, it is absent in a substantial minority. To date, no prognostic factors, other than genotype lb, have been identified that accurately predict these dissimilar outcomes. The natural history of recurrent hepatitis C varies. Historically, it has been regarded as generally benign. However, with increasing numbers of patients transplanted for hepatitis C it is now clear that a subgroup of patients develops severe progressive cholestatic hepatitis associated with allograft failure and death without retransplantation. Within 5 years following OLT, approximately 15–20% of patients progress to chronic active hepatitis and another 15–20% become cirrhotic. A minority of patients develop glomerulopathy or vasculitis, which are often associated with cryoglobulinaemia. The impact of immunosuppressive medications and rejection episodes on histopathological recurrence of progressive hepatitis C remains controversial and requires further studies. Although actuarial survival rates of patients transplanted for hepatitis C differ among transplantation centres, it appears that histopathological recurrence of hepatitis C does have an adverse impact on actuarial survival compared to the survival of patients transplanted for autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and metabolic liver diseases. When allograft failure develops in patients with recurrent hepatitis C, retransplantation is indicated, even though recent reports indicate that mortality may be increased, especially with concurrent renal insufficiency.

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

BACKGROUND/AIMS An experimental study has shown that propylthiouracil increases portal blood flow in normal rats. Whether propylthiouracil has a similar effect in patients with alcoholic cirrhosis remains to be demonstrated. The aim of this study was to evaluate the effects of oral propylthiouracil (300 mg) on systemic and portal hemodynamics in patients with alcoholic cirrhosis. METHODS Plasma propylthiouracil levels were also measured by high performance liquid chromatography in five patients with alcoholic cirrhosis. In eight patients with cirrhosis, mean arterial pressure, cardiac output and portal blood flow were evaluated before and after placebo and propylthiouracil administration. Hemodynamic measurements were performed by the Doppler technique. The plasma peak level of propylthiouracil was achieved at 1.4 +/- 0.1 h in patients with alcoholic cirrhosis. This time was chosen to express hemodynamic changes. RESULTS Propylthiouracil administration caused a significant increase in portal blood flow (+16.5%, p < 0.05) in patients with alcoholic cirrhosis. This effect was associated with a mild and significant rise in cardiac output (from 5.8 +/- 0.2 to 6.1 +/- 0.3 l/min, p < 0.05) and a decrease in peripheral vascular resistance (from 1171 +/- 69 to 1070 +/- 67 dyn . s-1 . cm-5, p < 0.01). A significant correlation was observed between changes in portal blood flow and peripheral vascular resistance (r = 0.79, p < 0.05). No significant changes were observed after placebo. CONCLUSIONS Our findings show that propylthiouracil has a vasodilatory effect in patients with alcoholic cirrhosis. We postulate that this effect could be the mechanism by which propylthiouracil decreases hypermetabolic state, and increases oxygen delivery to the liver, in patients with alcoholic liver diseases.

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis

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.