minocycline and Liver-Failure--Acute

We present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

Topics: Anti-Bacterial Agents; Diagnosis, Differential; Female; Humans; Liver Failure, Acute; Minocycline; Young Adult

Encephalopathy and brain edema are serious central nervous system complications of liver failure. Recent studies using molecular probes and antibodies to cell-specific marker proteins have demonstrated the activation of microglial cells in the brain during liver failure and confirmed a central neuroinflammatory response. In animal models of ischemic or toxic liver injury, microglial activation and concomitantly increased expression of genes coding for proinflammatory cytokines in the brain occur early in the progression of encephalopathy and brain edema. Moreover, the prevention of these complications with mild hypothermia or N-acetylcysteine (two treatments known to manifest both peripheral and central cytoprotective properties) averts central neuroinflammation due to liver failure. Recent studies using anti-inflammatory agents such as ibuprofen and indomethacin have shown promise for the treatment of mild encephalopathy in patients with cirrhosis, whereas treatment with minocycline, a potent inhibitor of microglial activation, attenuates the encephalopathy grade and prevents brain edema in experimental acute liver failure. The precise nature of the signaling mechanisms between the failing liver and central neuroinflammation has yet to be fully elucidated; mechanisms involving blood-brain cytokine transfer and receptor-mediated cytokine signal transduction as well as a role for liver-related toxic metabolites such as ammonia have been proposed. The prevention of central proinflammatory processes will undoubtedly herald a new chapter in the development of agents for the prevention and treatment of the central nervous system complications of liver failure.

Topics: Acetaminophen; Acetylcysteine; Animals; Brain Edema; Hepatic Encephalopathy; Humans; Hypothermia, Induced; Liver Failure, Acute; Minocycline

An 81-year-old female experiencing high fever, fatigue, and loss of appetite was admitted to our hospital and diagnosed with acute cholecystitis. Her condition did not improve and an eschar and erythema subsequently appeared. We then diagnosed Japanese spotted fever (JSF). She recovered immediately after the administration of minocycline. This case differed from other cases because the patient had a remarkably acute hepatic failure.. Considering that the present case might be associated with other factors, we performed a repeat polymerase chain reaction (PCR) test on the patient's blood that had been collected on admission and stored.. Epstein-Barr virus (EBV) was detected in her blood by PCR.. We consider this case might be associated with EBV.

Topics: Aged, 80 and over; Anti-Bacterial Agents; Cefoperazone; Cholecystitis, Acute; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Liver Failure, Acute; Minocycline; Polymerase Chain Reaction; Rickettsia; Rickettsia Infections; Sulbactam

Encephalopathy and brain edema are serious complications of acute liver failure (ALF). The precise pathophysiologic mechanisms responsible have not been fully elucidated but it has been recently proposed that microglia-derived proinflammatory cytokines are involved. In the present study we evaluated the role of microglial activation and the protective effect of the anti-inflammatory drug minocycline in the pathogenesis of hepatic encephalopathy and brain edema in rats with ALF resulting from hepatic devascularisation. ALF rats were killed 6 h after hepatic artery ligation before the onset of neurological symptoms and at coma stages of encephalopathy along with their appropriate sham-operated controls and in parallel with minocycline-treated ALF rats. Increased OX-42 and OX-6 immunoreactivities confirming microglial activation were accompanied by increased expression of interleukins (IL-1beta, IL-6) and tumor necrosis factor-alpha (TNF-alpha) in the frontal cortex at coma stage of encephalopathy in ALF rats compared with sham-operated controls. Minocycline treatment prevented both microglial activation as well as the up-regulation of IL-1beta, IotaL-6 and TNF-alpha mRNA and protein expression with a concomitant attenuation of the progression of encephalopathy and brain edema. These results offer the first direct evidence for central proinflammatory mechanisms in the pathogenesis of brain edema and its complications in ALF and suggest that anti-inflammatory agents may be beneficial in these patients.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain; Brain Edema; Cytokines; Hepatic Encephalopathy; Inflammation Mediators; Liver Failure, Acute; Male; Minocycline; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

In the present study, the effects of minocycline on progression of encephalopathy and brain edema in rats with acute liver failure (ALF) resulting from hepatic devascularization were studied in relation to the antioxidant action of the drug. ALF rats were sacrificed at precoma and coma stages of encephalopathy along with their appropriate sham-operated controls. Minocycline-treated ALF rats were sacrificed in parallel with comatose vehicle-treated ALF controls. Microglial activation was assessed using CD11b/c (OX-42) immunohistochemistry. Nitrite/nitrate levels in plasma and brain were measured using the Griess reaction. Expression of nitric oxide synthase (NOS) isoforms and heme oxygenase-1 (HO-1) were measured using real-time quantitative PCR and Western blot analysis. Increased nitrite/nitrate levels were observed in the plasma of ALF rats at coma stage of encephalopathy compared to sham-operated controls. Increased expression of HO-1 mRNA and protein was observed in the frontal cortex of ALF rats at both precoma and coma stages of encephalopathy. Significant increases in expression of endothelial (eNOS) and inducible (iNOS) isoforms of NOS mRNA and protein occurred only at coma stages of encephalopathy accompanied by increased brain nitrite/nitrate concentrations. As expected, minocycline attenuated microglial activation as confirmed by decreased OX-42 immunoreactivity, normalized nitrite/nitrate levels in brain and significantly attenuated HO-1, eNOS and iNOS expression. These results indicate that the beneficial effect of minocycline on the neurological complications of ALF is mediated, at least in part, by reduction of oxidative/nitrosative stress.

Topics: Ammonia; Animals; Blotting, Western; Brain; Brain Chemistry; Disease Progression; Heme Oxygenase-1; Hepatic Encephalopathy; Immunohistochemistry; Isoenzymes; Liver Failure, Acute; Male; Minocycline; Nitrates; Nitric Oxide Synthase; Nitrites; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Nitrogen Species; Reverse Transcriptase Polymerase Chain Reaction; Water

Topics: Acne Vulgaris; Adult; Anti-Bacterial Agents; Female; Follow-Up Studies; Humans; Liver Failure, Acute; Liver Transplantation; Minocycline

1. Minocycline has anti-inflammatory and antiapoptotic effects on cartilage, neurons and periodontal tissues, and both properties are central to the pharmaceutical treatment of liver diseases. We investigated the effects of minocycline on fulminant hepatitis in C57BL/6J mice induced by lethal challenge of the activating anti-Fas antibody, Jo2. 2. Intraperitoneal injection of Jo2 (0.6 microg g(-1)) to mice resulted in fulminant hepatitis, as evidenced by increase of serum alanine/aspartate transaminase activities and histopathological alterations in liver sections, as well as animal death. Nevertheless, mice pretreated with three doses of minocycline (5 mg kg(-1)) resisted this lethal effect significantly. Minocycline treatment improved the survival kinetics, although to a lesser extent, when mice were challenged simultaneously with Jo2 or even treated 30 min after the lethal challenge. 3. Jo2-induced activation of caspase-3 or -9 in liver tissues was inhibited by minocycline pretreatment, and yet the direct addition of minocycline to liver extracts from Jo2-challenged mice failed to block caspase activation in vitro. Moreover, minocycline efficiently suppressed the release of cytochrome c from mitochondria of the liver tissues from Jo2-challenged mice. In contrast, caspase-8 activation and Bid truncation triggered by Jo2 were not diminished by minocycline pretreatment in mouse livers. 4. Our results suggest that easing of Fas-triggered fulminant hepatitis by minocycline may involve a mitochondrial apoptotic pathway, probably through preventing cytochrome c release and thereby blocking downstream caspase activation.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Dose-Response Relationship, Drug; fas Receptor; Liver; Liver Failure, Acute; Male; Mice; Mice, Inbred C57BL; Minocycline; Receptors, Tumor Necrosis Factor

This report describes a 15-year-old white boy who presented with fever, back pain, a disseminated exanthematous rash, renal failure, and hepatopathy 3 weeks after the initiation of oral minocycline therapy for facial acne. Marked peripheral and urine eosinophilia were noted. A bone marrow aspiration showed more than 50% eosinophils without any evidence of malignancy, and a simultaneous kidney biopsy showed acute interstitial nephritis (AIN). The patient's symptoms and laboratory findings improved after high-dose steroid therapy was initiated, worsened when it was withheld, and improved again after it was reinitiated in view of the biopsy findings. The patient recovered completely, and steroids were tapered to discontinuation over 3 months. Over a year later, the patient's peripheral blood mononuclear cells (PBMCs) were cultured for 2 weeks in the presence or absence of minocycline ex vivo, and minocycline was found to induce the emergence of CD4(+) cells after 1 week in culture. In conclusion, this article shows for the first time several new aspects of minocycline-induced morbidity: renal and hepatic failure can occur together, and AIN and elevated blood eosinophil counts can be accompanied by marked bone marrow eosinophilia, suggesting a systemic allergic response as the underlying pathomechanism. Furthermore, the initial phase of such a response appears to involve CD4(+) T cells detectable ex vivo. Lastly, high-dose treatment with corticosteroids appears to be beneficial in this setting.

Topics: Acne Vulgaris; Adolescent; CD4 Lymphocyte Count; Eosinophilia; Humans; Liver Failure, Acute; Male; Minocycline; Nephritis