Severe hepatocytotoxicity linked to denosumab.

OBJECTIVE: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab. CASE REPORT: A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis. CONCLUSIONS: We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.

Metabolic syndrome is associated with increased prevalence of advanced colorectal polyps.

OBJECTIVES: To examine the association between metabolic syndrome (MetS) and/or its components and colorectal neoplasms in adult population undergoing screening colonoscopy. DESIGN: Cross-sectional study. SETTING: Institute of Gastroenterology, Kaplan Medical Center, Rehovot, Israel. PARTICIPANTS: Two hundred ninety nine consecutive outpatients undergoing screening colonoscopy. MEASUREMENTS: MetS was determined according to the Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) criteria. Blood test results and other clinical data were retrieved from the electronic medical records. RESULTS: In 94 patients (31.8%) polyps were detected. Thirty two (34%) of the polyps were advanced. Eighty one percent of patients with an advanced polyp met the criteria for MetS. About the same MetS prevalence (84%) was found in men, but not in women. An advanced polyp was detected in 14% of patients with MetS, compared to 5% of patients without MetS. Odds ratio for having an advanced polyp in a patient with MetS compared to a patient without MetS was 10.64. CONCLUSION: MetS was found to be a risk factor for advanced polyps. This association is suggestive of the need that patients with MetS should be urged to have a screening colonoscopy.

Liver injury induced by anticancer chemotherapy and radiation therapy.

Cytotoxic chemotherapy prolongs survival of patients with advanced and metastatic tumors. This is, however, a double-edged sword with many adverse effects. Since the liver has a rich blood supply and plays an active role in the metabolism of medications, it is not surprising that there can be hepatic injury related to chemotherapy. In addition, radioembolization may affect the parenchyma of normal and cirrhotic livers. We review chemotherapy-associated liver injury in patients with colorectal liver metastases, including downsizing chemotherapy and neoadjuvant chemotherapy. We discuss the mechanism of the hepatic injury, secondary to reactive oxygen species, and the spectrum of hepatic injury including, steatosis, steatohepatitis, hepatic sinusoidal injury and highlight the pharmacogenomics of such liver insults. Methods for reducing and treating the hepatotoxicity are discussed for specific agents including tamxifen and the newly introduced targeted antibodies.

Mortality predictors in hospitalized elderly patients.

AIM: To find out which of the two predictors, Charlson co-morbidity index or vitamin B12, better estimates the risk of in-hospital mortality in seriously ill patients. METHOD: Electronic hospital records of 1509 elderly patients aged 65 and older were retrospectively surveyed. RESULTS: Albumin, age and elevated vitamin B12 levels were significantly associated with increased in-hospital mortality. Charlson co-morbidity index was not significantly associated with death. The highest mortality (24.3%) was found in the group of patients who were concomitantly in the lowest albumin quartile and the highest vitamin B12 levels quartile. In this group, mortality increased significantly with age. By elasticity calculation, vitamin B12 capability to predict mortality was higher by ≈ 3 times than that of Charlson co-morbidity index. CONCLUSION: In view of the fact that vitamin B12 levels have been found to predict mortality, they should be measured in geriatric practice, in addition to albumin levels, as a practical and reliable tool for identifying high risk elderly hospitalized patients. Probably, a combination of two or more available and inexpensive routinely taken tests can give a better estimation of mortality than some complicated tools, like Charlson co-morbidity index.

Prostatic zinc and prostate specific antigen: an experimental evaluation of their combined diagnostic value.

PURPOSE: In cancer affected prostate cells lose the ability to concentrate zinc, resulting in a substantial decrease in Zn in the prostate. We investigated the possibility of using prostatic zinc combined with prostate specific antigen (PSA) as a novel tool for the reliable diagnosis of prostate cancer. MATERIALS AND METHODS: Using the x-ray fluorescence method the Zn concentration was determined in vitro in prostate samples extracted by surgery from 28 patients. Clinical records included age, serum PSA, sextant prostate needle biopsy, previous medical therapy, surgical procedure and histological findings. RESULTS: A new relationship was found between Zn in prostate tissue and PSA in blood, which allows improved separation between prostate cancer and benign prostate hyperplasia, and might have a significant impact on the reliable diagnosis of prostate cancer. CONCLUSIONS: Zn concentration is not uniform even in the same anatomical region of the prostate, so that a number of measurements at various locations are required for a diagnostic procedure. The most interesting finding in this study is the relationship between Zn concentration and PSA. A combination of these parameters represents a significant improvement on the diagnostic value of each of them separately and provides a powerful tool for more accurate diagnosis. Although the method may be applied in vitro on biopsy samples, our study underlines the importance of developing a facility for in vivo Zn determination in the prostate.

Acute hepatitis E virus infection presenting as a prolonged cholestatic jaundice.

Hepatitis E virus (HEV) is an enteric virus that usually causes a self-resolving hepatitis; although, it may be fatal, especially in pregnant women. Although HEV is endemic in Israel, there have been no recent local outbreaks. We report the case of a 70-year-old man who presented with painless jaundice. Ultrasound and abdominal computed tomography scan revealed gallstones, with no evidence of cholecystitis and no dilatation of the intra-or extrahepatic bile ducts. An open cholecystectomy was performed with intraoperative cholangiography. There was no evidence of choledocholithiasis. A subsequent endoscopic retrograde cholangiopancreatography was normal. His bilirubin level subsequently increased to a maximum of 25 mg/dL, and his gamma-glutamyl-transferase level reached 1,400 U/L. There was no evidence of any autoimmune or metabolic disease, and routine viral serology was normal except for immunoglobulin G to hepatitis A virus. A liver biopsy revealed an acute cholestatic picture. The jaundice resolved slowly after a period of 6 months. Hepatitis E virus RNA was isolated from the acute-phase serum and was not detectable in the convalescent serum. This case is a unique example of chronic cholestatic jaundice that we think is caused by acute HEV infection.

Cardiac tamponade as a manifestation of tuberculosis.

Tuberculosis has been increasing in incidence in recent years. Pericardial involvement and pericardial effusions are well-documented and may result in pericardial tamponade. Despite this, large pericardial effusions are uncommon, and manifestation as cardiac tamponade is rare. We report two cases of tuberculous pericarditis in which the initial feature was tamponade. Since the diagnosis of tuberculosis may be delayed due to the slow-growing nature of the bacterium, physicians need to be aware of this possibility and consider the use of modern diagnostic techniques that may permit an earlier diagnosis.

[Effective treatment with Lamivudine of patients with reactivation of hepatitis B following chemotherapy administration].

Chemotherapy administration to patients with lymphoproliferative diseases that are carriers of hepatitis B can be complicated by reactivation of Hepatitis B. This may lead to morbidity and mortality due to liver failure. We report 2 cases, treated recently. The first case is that of a 63-year-old female with a diagnosis of immunoblastic lymphoma. The patient was treated with the ProMACE-CytaBOM protocol. During treatment Hepatitis B was reactivated and after termination, of chemotherapy she developed fulminant hepatitis with hyperbilirubinemia, coagulopathy, hypoalbuminemia and ascites. The second case is that of a 34 years old male with a diagnosis of T-ALL who was treated according to the BFM 95 protocol. He had reactivation of Hepatitis B during induction therapy. These two patients were treated with Lamivudine with resolution of the hepatitis and disappearance of HBV DNA from the sera. Prophylactic administration of Lamivudine enabled reinduction of chemotherapy in the first case after relapse of the lymphoma and continuation of BFM 95 protocol in the second patient. Lamivudine inhibits replication of hepatitis B virus and prevents reactivation of Hepatitis B during immunosuppression induced by chemotherapy and probably ameliorates the severity of already reactivated hepatitis.

Treatment of chronic hepatitis C virus infection.

OBJECTIVE: To review the literature on the treatment of chronic hepatitis C virus (HCV) infection. DATA SOURCES: MEDLINE search (1986-December 1999) using key words such as HCV, hepatitis, non-A and non-B hepatitis, as well as terms regarding treatment during that time period. DATA SYNTHESIS: HCV infection was initially treated with interferon monotherapy, but only a minority of patients responded to long-term therapy. A higher rate of response in both interferon-naïve patients and interferon-relapsers has been achieved by using the combination of interferon and ribavarin. Other treatment regimens including high-dose interferon protocols, ursodeoxycholic acid, amantadine, and nonsteroidal antiinflammatory drugs have been less promising. Many alternative therapies are being investigated. CONCLUSIONS: HCV infection is a major public health problem. It is now possible to achieve a cure in nearly 50% of the patients with this infection. Many additional therapies are being evaluated in order to achieve a higher cure rate.

Anticardiolipin autoantibodies in serum samples and cryoglobulins of patients with chronic hepatitis C infection.

OBJECTIVE: Chronic hepatitis C virus (HCV) has been linked to extrahepatic autoimmune phenomena. In addition, a variety of autoantibodies are found in patients with HCV. The prevalence, nature, and clinical significance of anticardiolipin (aCL) autoantibodies in serum samples of patients with HCV were therefore investigated. PATIENTS AND METHODS: A prospective study of 48 consecutive patients with chronic HCV with no evidence of previous hepatitis B virus (HBV) infection or any other autoimmune disorder. Thirty patients with HBV and 50 healthy volunteers matched for age and sex served as control groups. Anticardiolipin antibodies in the serum samples and cryoprecipitates were measured by a sensitive enzyme linked immunosorbent assay (ELISA). The beta(2) glycoprotein I (beta(2)-GPI) dependency was determined by carrying out aCL assays in the presence or absence of fetal calf serum samples. RESULTS: High levels of IgG aCL antibodies were detected in serum samples of 21/48 (44%) patients with HCV. These autoantibodies showed no beta(2)-GPI dependency. The control groups had much lower levels of aCL antibodies (20% in the patients with HBV and none in the normal volunteers). Cryoprecipitates from four patients with HCV (three aCL positive; one aCL negative) were further isolated. In two of the three aCL positive patients, specific cardiolipin reactivity was shown in the cryoprecipitates. The group of patients with HCV and aCL antibodies in their serum showed significantly higher total IgG levels, a higher incidence of antinuclear antibodies, and viraemia (HCV RNA) than the aCL negative patients. None of the patients with HCV and aCL antibodies showed any clinical manifestations related to those autoantibodies. CONCLUSIONS: This study clearly shows a high prevalence of IgG aCL antibodies in the serum of patients with HCV and the localisation of these antibodies in some cryoprecipitates. The role of these autoantibodies on the course of HCV infection and their clinical significance has not yet been determined.