Prednisone liver
Looking for:
- Effect of liver function on the metabolism of prednisone and prednisolone in humans |
- Prednisone liver
Corticosteroids - LiverTox - NCBI Bookshelf
- Prednisone liver
The cause of this apparent hepatotoxicity is not known, but it may represent severe autoimmune hepatitis triggered by the sudden profound immunosuppression and subsequent immune reconstitution.
Importantly, symptoms and jaundice develop 1 to 6 weeks after stopping methylprednisolone and the pattern of serum enzyme elevations is typically hepatocellular. These episodes can be symptomatic and severe.
Immunoallergic manifestations are uncommon and autoantibodies may not be present. Several instances have resulted in acute liver failure resulting in death or need for emergency liver transplantation. But transient injury without symptoms can also occur accompanied by serum aminotransferase elevations that are 10 to 40 times the ULN.
Restarting corticosteroids may be appropriate for this syndrome particularly if symptomatic, but this approach has not been evaluated systematically and many instances have resolved spontaneously. Recurrence of injury, often in a more rapid and severe form, arises upon reexposure to high dose pulse methylprednisolone. Strangely, it is not clear whether this syndrome can be induced by high dose intravenous prednisone or dexamethasone. Likelihood score : A[HD] well established cause of liver injury when given in high doses, either the result of reactivation of hepatitis B, or an acute hepatocellular injury after high dose intravenous treatment, particularly with methylprednisolone.
Budesonide is also a corticosteroid but has not been linked to liver injury and is discussed separately in LiverTox. A 34 year old woman with systemic lupus erythematosus was treated with betamethasone with good clinical response with improvements in rash, fatigue and laboratory tests.
Over a 6 month period, the daily dosage was gradually decreased from 5 to 1. Her weight had risen by 11 kilograms and she had firm hepatomegaly. Laboratory tests showed elevations in serum aminotransferase levels, but normal serum bilirubin, albumin, and prothrombin time.
Testing for HBsAg was negative. She was known to be positive for antinuclear antibody She denied alcohol use, which was confirmed by family members and friends. A liver biopsy showed marked steatosis with inflammation including neutrophils, occasional Mallory bodies and mild central sinusoidal and portal fibrosis. Weight loss led to slight decreases in serum ALT levels. This is an early, but well documented report of nonalcoholic steatohepatitis arising during corticosteroid therapy.
The patient was evidently asymptomatic of liver disease, but the height of the serum aminotransferase elevations led to a hospital admission and liver biopsy. An issue is whether the liver disease was due to corticosteroid therapy directly or was the result of weight gain and insulin resistance caused by the therapy.
Betamethasone is a synthetic, high potency glucocorticoid; 1. A 69 year old man with ulcerative colitis and the HBsAg carrier state developed jaundice and hepatitis after 9 months of continuous prednisolone therapy and shortly after intravenous pulse treatment with methylprednisolone. Because of relapsing ulcerative colitis, he was started on prednisolone therapy in tapering doses 60 mg daily down to 5 mg daily.
Approximately 8 months into therapy, he received a 7 day course of intravenous methylprednisolone. One week later, while still on low doses of oral prednisolone, he developed fatigue and nausea. He was admitted. On examination, he was jaundiced and had mild mental dullness and asterixis. In addition he had IgM anti-HBc. Despite initiation of lamivudine therapy for hepatitis B and intensive medical management, he developed progressive liver failure, coagulopathy, hepatic coma and died 25 days after admission.
Autopsy was refused. Reactivation of hepatitis B in an HBsAg carrier can be followed by a severe episode of hepatitis as immunosuppression is withdrawn. Many cases present as "acute-on-chronic" liver failure rather than classical acute liver failure. The prognosis is poor and antiviral therapy appears to have little effect once hepatic failure is present. A 43 year old woman with Graves disease developed worsening ophthalmopathy despite adequate control of thyroid function.
Over the next six weeks, serum aminotransferase levels rose further Table , with no or only minor elevations in serum alkaline phosphatase, gamma glutamyltranspeptidase and bilirubin.
Tests of hepatitis A, B and C were negative. Immunoglobulin levels were normal and tests for autoantibodies, including antinuclear antibody, smooth muscle antibody and liver-kidney microsomal antibody, were negative. A liver biopsy showed changes suggestive of chronic aggressive hepatitis with marked lymphocytic inflammation, interface hepatitis, and both focal and bridging necrosis.
Because the histological and clinical features supported the diagnosis of severe autoimmune hepatitis, oral prednisone was initiated, with prompt improvements in serum aminotransferase levels. Prednisone doses were gradually reduced and ultimately withdrawn. Serum enzymes were normal within 2 months of starting prednisone and the dosage was gradually reduced and then withdrawn 3 months after initiation. An example of an acute hepatitis-like syndrome arising after pulse methylprednisolone therapy.
These episodes arise typically 2 to 4 weeks after an early cycle of pulse therapy, and range in severity from an asymptomatic and transient rise in serum aminotransferase levels to an acute hepatitis and even fulminant hepatic failure.
In this instance, the marked and persistent rise in serum enzymes coupled with liver histology suggesting chronic hepatitis led to a diagnosis of new-onset autoimmune hepatitis, despite the absence of serum autoantibodies or hypergammaglobulinemia. Autoimmune hepatitis may initially present in this fashion, without the typical pattern of serum autoantibodies during the early, anicteric phase. The diagnosis was further supported by the prompt improvements in serum enzymes with prednisone therapy.
The acute hepatitis-like syndrome that can occur after pulses of methylprednisolone is best explained as a triggering of an underlying chronic autoimmune hepatitis caused by the sudden and profound immunosuppression followed by rapid withdrawal. This syndrome can be severe, and fatal instances have been reported. Whether reinitiation of corticosteroid therapy with gradual tapering and withdrawal is effective in ameliorating the course of illness is unclear, but anecdotal reports suggest that they are beneficial and should be initiated promptly.
Long term follow up of such cases is also necessary to document that the autoimmune hepatitis does not relapse once corticosteroids are ultimately withdrawn again. Turn recording back on. Help Accessibility Careers. Drug Records. Search term. Corticosteroids Last Update: May 7, OVERVIEW Introduction The corticosteroids are a group of chemically related natural hormones and synthetic agents that resemble the human adrenal hormone cortisol and have potent antiinflammatory and immunosuppressive properties and are widely used in medicine.
Hepatotoxicity, Mechanism of Injury Corticosteroids have multiple adverse side effects, due to their multiplicity of actions affecting virtually all organs. Nonalcoholic steatohepatitis after long term corticosteroid therapy. Key Points View in own window Medication: Betamethasone 1. Comment This is an early, but well documented report of nonalcoholic steatohepatitis arising during corticosteroid therapy.
Case 2. Reactivation of chronic hepatitis B by corticosteroids. Comment Reactivation of hepatitis B in an HBsAg carrier can be followed by a severe episode of hepatitis as immunosuppression is withdrawn.
Case 3. Severe acute hepatitis following bolus, high dose methylprednisone therapy. Comment An example of an acute hepatitis-like syndrome arising after pulse methylprednisolone therapy. Nonalcoholic fatty liver with alcoholic hyaline after long-term glucocorticoid therapy. Acta Hepato-Gastroenterologica. Dtsch Med Wochenschr.
Autoimmune hepatitis during intravenous glucocorticoid pulse therapy for Graves' ophthalmopathy treated successfully with glucocorticoids themselves. J Endocrinol Invest. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. Philadelphia: Lippincott, , pp.
Expert review of hepatotoxicity of corticosteroids, focusing upon fatty liver and alcoholic hyaline-like changes with high doses or long term low doses.
Chitturi S, Farrell GC. Adverse effects of hormones and hormone antagonists on the liver. Drug-induced liver disease.
Amsterdam: Elsevier, , pp. Review of liver injury from corticosteroids mentions hepatic steatosis and acute liver injury following high dose methylprednisolone.
Adrenocortical steroids. ACTH, adrenal steroids, and pharmacology of the adrenal cortex. New York: McGraw-Hill, , pp.
Textbook of pharmacology and therapeutics. Hepatomegaly with fatty infiltration secondary to cortisone therapy: case report. Production of fatty liver in the rat by cortisone. Proc Soc Exp Biol Med. Hepatomegaly following short-term high-dose steroid therapy.
J Pediatr Gastroenterol Nutr. A short course of prednisolone in chronic type B hepatitis. Report of a randomized, double-blind, placebo-controlled trial. Ann Intern Med. Abnormal liver-function tests associated with long-term systemic corticosteroid use in subjects with asthma. J Allergy Clin Immunol. Two fatal cases of hepatitis B virus carriers after corticosteroid therapy for bronchial asthma.
Intern Med. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterol Clin Biol. Subacute severe steatohepatitis during prednisolone therapy for systemic lupus erythematosis. Am J Gastroenterol. Severe exacerbation of hepatitis after short-term corticosteroid therapy in a patients with "latent" chronic hepatitis B. Weissel M, Hauff W. Fatal liver failure after high-dose glucocorticoid pulse therapy in a patient with severe thyroid eye disease.
Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study.
J Clin Endocrinol Metab. Acute severe steatohepatitis related to prednisolone therapy. Drug-induced steatohepatitis. Clin Liver Dis. Steatohepatitis during methylprednisolone therapy for ulcerative colitis exacerbation. J Intern Med. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves' ophthalmopathy. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto's thyroiditis: case report.
Acute hepatitis related to prednisolone. Eur J Intern Med. Recurrent acute hepatitis in patient receiving pulsed methylprednisolone for multiple sclerosis. Indian J Gastroenterol. Methylprednisolone-induced toxic hepatitis. Ann Pharmacother. Autoimmune hepatitis after high-dose intravenous methylprednisolone pulse in RR-MS.
CEJ Med. Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy. Development of autoimmune hepatitis type 1 after pulsed methylprednisolone therapy for multiple sclerosis: a case report. World J Gastroenterol. Rev Esp Enferm Dig. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.
Hoofnagle JH. Reactivation of hepatitis B. Hepatotoxicity after high-dose methylprednisolone for demyelinating disease. Clin Neuropharmacol. Drug-induced acute liver failure: results of a U.
Liver injury induced by high-dose methylprednisolone therapy: a case report and brief review of the literature. Hepat Mon. Recurrent high-dose intravenous methylprednisolone succinate pulse therapy-induced hepatopathy in a patient with multiple sclerosis.
Med Princ Pract. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Acute liver toxicity due to methylprednisolone: consider this diagnosis in the context of autoimmunity. Clin Res Hepatol Gastroenterol. High-dose methylprednisolone-induced hepatitis in a patient with multiple sclerosis: a case report and brief review of literature.
Neth J Med. Methylprednisolone-induced liver injury: a diagnostic challenge. Isr Med Assoc J. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol. Juan J, Feld JJ. Hepatitis B virus and hepatitis C virus treatment and management in patients receiving immune-modifying agents.
Curr Opin Rheumatol. Methylprednisolone-induced toxic hepatitis after intravenous pulsed therapy for multiple sclerosis relapses. High-dose intravenous methylprednisolone: liver injury.
No significant difference in survival between the two groups was achieved. Another steroid trial in ALF from the US included 62 patients with fulminant drug-induced hepatotoxicity Rakela et al. Based on this study, the European Association for the Study of the Liver recommended discontinuing steroid treatment in patients with ALF.
Auto-antibodies are frequent in patients with ALF. Bernal et al. Steroid therapy was not associated with improved overall survival or improved survival in any of these categories.
In those patients with highest Model for End stage Liver disease MELD scores, steroid treatment was even associated with a worse outcome. As the authors pointed out, it is conceivable that the lack of benefit of steroid use might be due to selection bias.
Thus, patients who received steroids might have been more ill. However, MELD scores were similar in the two groups and the international normalized ratio of prothrombin time INR was actually higher in those who did not receive steroids.
The authors postulated that higher ALT might be a surrogate marker for an inflammatory process that might be sensitive to corticosteroid therapy Karkhanis et al. In other words, the action of the drug can affect the balance in the immune system and therefore induce various immune mediated adverse effects. Similar results have been reported from larger cohorts Miller et al.
In the study of Huffman et al. Twelve of 17 were diagnosed after treatment with ipilimumab, three were diagnosed after pembrolizumab, and 2 after ipilimumab combined with nivolumab. Patients were most commonly treated with systemic corticosteroids such as prednisone.
Immunosuppression was tapered over a median of 42 days; in three patients steroids had to be reinitiated due to clinical or laboratory worsening of liver enzymes.
Normalization of liver tests was seen within a median of 1 month after start of immunosuppression. Time to onset varied from 2—24 weeks after initiation of treatment median 4—16 weeks. DILI due to CPIs has a distinct biochemical and histological phenotype, and often occurs together with other immune-mediated adverse reactions.
Clinical guidelines from oncologists recommend high-dose corticosteroids in patients with moderate to severe CPI-induced hepatotoxicity. If the ALT elevation is accompanied by a rise in bilirubin, steroid treatment should be started immediately.
Oral prednisone 0. No clinical trial has been conducted to demonstrate the efficacy of steroids in general and high steroid doses in particular in this patient population. Guidline recommendations are mainly empirical and based on recommendations provided in the clinical trial protocols Puzanov et al.
De Martin et al. These results have mostly been reproduced by other groups Gauci et al. The study by Ito et al. Thirteen patients were treated with steroids steroid group, SG , whereas eight were not non-steroid group, NSG. Only one patient had an unfavourable outcome. Higher aminotransferases and bilirubin levels and lower prothrombin levels were observed in the SG than in the NSG Gauci et al.
The authors concluded that many patients with moderate to severe immune mediated hepatitis due to CPIs can be managed without steroids and suggested that steroid therapy should be considered in patients with high bilirubin and prothrombin values.
A management protocol was proposed for validation in large, prospective cohorts Gauci et al. There is little data published on adverse effects of high-dose corticosteroid treatment in patients with DILI.
Generally, corticosteroid use can be associated with undesirable side effects, such as diabetes mellitus DM , osteoporosis, hypertension, infections and psychosis. Nevertheless, it seems that the administration of corticosteroids in DILI has not been reported as detrimental in these patients. Mild adverse effects of corticosteroid treatment in patients with DILI have though been reported in some studies Hu et al. Among 53 patients receiving corticosteroids for DILI, three patients developed respiratory infections successfully treated with antibiotics , two patients with DM had uncontrolled increase of blood glucose, one experienced mental disturbances, and another one hypertension.
Since steroids improved survival in that particular study and was associated with improvement in the liver injury, the authors strongly recommended short-term administration of steroids in severe DILI patients Hu et al.
Among them, 66 patients were receiving a median dose of 40 mg prednisone per day, while 24 patients composed the control group.
However, Faje et al. It was the first study reporting a potentially negative impact of corticosteroids on the efficacy of CPI treatment. In summary, corticosteroid administration in patients with DILI is usually well tolerated, although this has not been systematically reported. Some adverse effects of corticosteroids are worrisome, particularly if higher steroid doses are used, and clinicians should carefully evaluate each case for benefits and risks.
Corticosteroids are often used in the treatment of DILI. However, their efficacy and safety are still disputable. Based on the available knowledge, patients with severe DILI or DI-AIH might benefit from steroid therapy, although evidence based on randomized controlled trials is largely lacking. Steroid therapy is not evidence based and its impact on patient outcomes is not clear.
Therefore, indication, dose and duration of steroid therapy should be investigated in randomized controlled trials to fill the lack of evidence in the current treatment guidelines regarding efficacy, survival and side effects.
EB designed the review and wrote the first draft. All authors approved the final version of the manuscript for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Bernal, W. Hepatology 51 6 , — Online ahead of print. Borlak, J. Liver Int. Brahmer, J. Chalasani, N. Gastroenterology , —4.
Cheung, V. Frontline Gastroenterol. De Martin, E. Del Castillo, M. European Association for the Study of the Liver Gut 20, — Faje, A. Cancer 18 , — Ferrero, D. Haematologica 91 6 Suppl. Gauci, M. Germani, G. Minerva Gastroenterol. Ghabril, M. Haanen, J. Hoofnagle, J. Hou, F.
Hu, P. Huffman, B. Ito, T. Karkhanis, J. Steroid Use in Acute Liver Failure. Hepatology 59 2 , — Kirk, A. Gut 21 1 , 78— Kitagataya, T. Miller, E. Ostapowicz, G. Pang, L. Parlati, L. Pollack, M. Puzanov, I.
Journal of Translational Medicine volume 12Article number: Cite this article. Metrics details. Contradictory evidence has been published on the effects of steroid treatments on the outcomes of kidney and liver transplantation from brain dead BD donors.
Our study aimed to evaluate this disparity by investigating the effect of prednisolone administration on BD rats. BD induction was performed in ventilated rats by inflating a Fogarty catheter placed in the epidural space.
Prednisolone After four hours of determination of BD: serum, kidney and liver tissues samples were collected and stored. RT-qPCR, routine biochemistry and immunohistochemistry were performed. Polymorphonuclear influx assessed by histology, and inflammatory gene expression were reduced in the kidney and liver.
However, complement component 3 C3 expression was decreased in kidney but not in liver. Gene expression of HSP, a cytoprotective protein, was down-regulated in the liver after treatment.
This study shows that prednisolone decreases inflammation and improves renal function, whilst not reducing liver injury. The persistence of complement activation and the negative effect on protective cellular mechanisms in the liver may explain the disparity between the effects of prednisolone on the kidney and liver of BD rats.
The difference in the molecular and cellular responses to prednisolone administration may explain the contradictory evidence of the effects of prednisolone on different organ types from brain dead organ donors. The shortage of organs for transplantation remains one of the most important issues facing the transplant community today.
Increasingly, organs from brain dead extended criteria donors ECD and donors after circulatory arrest DCD are being used to address the organ deficit. The short and long term outcomes of allografts obtained from these donors are inferior when compared to living donors [ 12 ]. In the case of organs obtained from donors after brain death DBD it has been shown that HLA mismatched living donors have better outcomes even when cold ischemia times are taken into consideration [ 3 ].
The explanation for this lies in the process of brain death BD itself resulting in a non-physiological environment culminating in significant organ injury prior to organ procurement. The procurement, preservation and reperfusion phases of transplantation result in significant additional injury to the allograft rendering it susceptible short and long term dysfunction [ 4 — 6 ].
BD causes complex disturbances of normal homeostatic systems resulting in hemodynamic instability [ 7 — 10 ] hormonal impairment [ 11 — 13 ] and inflammation [ 14 — 17 ]. BD results in significant cerebral ischemia and intracranial hypertension resulting in parasympathetic activity followed by a severe vasoconstriction.
A progressive paralysis of the spinal cord occurs, this cause the loss of vasomotor tone and leads to hemodynamic instability which characterizes this period [ 18 — 20 ]. Pituitary function is also affected following BD as adrenocorticotrophic hormone ACTH secretion is altered resulting in a transient rise in cortisol levels, which then diminishes progressing below baseline levels.
BD results in a heightened systemic inflammatory state as illustrated by the influx of polymorphonuclear neutrophils PMNs into kidney and liver tissues [ 15 ]. The trigger for this inflammatory process is not well understood, however recent evidence suggests there could be a role for cerebral cytokines that cross the blood-brain barrier, in addition to complement activation [ 2223 ] and intestinal bacterial translocation [ 2425 ].
There is general consensus about the importance of maintaining hemodynamic stability, but hormonal or anti-inflammatory treatments remains controversial despite promising experimental evidence [ 21 ].
The administration of glucocorticoids to donors has been used as hormonal replacement therapy with a varied degree of success [ 26 — 31 ]. In BD glucocorticoid administration could have several beneficial effects including anti-inflammatory properties and the ability to augment chrommaffin cells production of endogenous epinephrine [ 32 ].
The anti-inflammatory effects of steroids result from the pleiotropic interaction with the glucocorticoid receptor. The cortisol-glucocorticoid receptor complex can act through genomic and non-genomic downstream signalling pathways within the cell. We hypothesize that prednisolone pre-treatment of BD rats could reduce the inflammatory response and improve the quality of kidney and liver allografts. The aim of this study is to assess the potential benefit of the prednisolone pre-treatment in the liver and kidney of BD rats.
Male adult Fisher F rats - g were used in all experiments. All animals received care in compliance with the guidelines of the local animal ethics committee according to Experiments on Animals Act issued by the Ministry of Public Health, Welfare and Sports of the Netherlands.
Brain death BD was induced as follows: animals were anesthetized using isoflurane with O2. A cannula was inserted in the femoral artery and vein for continuous mean arterial pressure MAP monitoring and fluid administration. Animals were intubated via a tracheostomy and ventilated throughout the experiment. Inflation of the balloon was terminated once the MAP began to improve after a characteristic period of hypotension, reflecting the autonomic storm.
BD was confirmed by the absence of corneal and pupillary reflexes and a positive apnea test. Following confirmation of BD, anesthesia was terminated but ventilation continued. A homeothermic blanket control system was used throughout the BD maintenance period. Four hours after determination of BD, rats were heparinized with IU heparin. A laparotomy was subsequently performed and blood collected from the aorta. Organs were flushed with 0. Rats were randomly assigned to each group.
Sham-operated rats served as controls and were ventilated for half an hour under anesthesia before termination. This was in accordance with the requirement of our local Animal Welfare Committee guidance for the use of sham controls in experiments. Prednisolone or saline was administered intravenously 30 minutes before the start of BD induction. Prednisolone dosage was chosen based on previous experiments and to give the best hemodynamic stability Plasma creatinine was determined in the biochemistry lab of the University Medical Center Groningen.
All samples were analyzed in duplicate and read at nm. Fragments of several genes were amplified with the primer sets outlined in Table 1. Pooled cDNA obtained from brain-dead rats were used as internal references. All samples were analyzed in triplicate. The latter stage was repeated 40 times. Primers were designed with Primer Express software Applied Biosystems and primer efficiencies were tested by a standard curve for the primer pair resulting from the amplification of serially diluted cDNA samples 10 ng, 5 ng, 2.
PCR efficiency were found to be 1. Real-time PCR products were checked for product specificity on a 1. Sections were fixated for 10 min using acetone. Next, sections were stained with HIS mAb supernatant, two times diluted using an indirect immunoperoxidase technique. Endogenous peroxidase was blocked using H 2 O 2 0. After thorough washing, sections were incubated with horseradish peroxidase-conjugated rabbit anti-mouse IgG as a secondary antibody for 30 mins, followed by goat anti-rabbit IgG as a tertiary antibody for 30 mins both from Dako, Glostrup, Denmark.
The reaction was developed using 9-amino-ethylcarbazole as chromogen and H 2 O 2 as substrate. Sections were counterstained using Mayer hematoxylin solution Merck, Darmstadt, Germany. Negative antibody controls were performed. Localization of immunohistochemical staining was assessed by light microscopy. For each tissue section, positive cells per field were counted in 10 microscopic fields of the tissue at 40x magnification. Results were presented as number of positive cells per glomerulus in the kidney and number of positive cells per field in the liver.
Statistical analyses were performed using Prism 5. Administration of NA was comparable between both groups saline: 0. Blood pressure registry. As a black-continuous line the mean in each minute of blood pressure for the prednisolone brain death group. As a grey-continuous line the mean in each minute for the saline brain death group. Plasma creatinine levels was significantly different between sham and BD animals treated with saline solution. Creatinine plasma levels in BD animals treated with prednisolone Plasmatic levels of kidney function markers and liver injury markers.
Assessing cellular liver injury, aspartate aminotransferase ASTalanine aminotransferase ALT and lactate dehydrogenase LDH plasma levels were significantly increased after BD in comparison to sham animals. Our results demonstrated a significant decrease in IL-6 levels in BD animals treated with prednisolone compared to BD animals treated with saline Figure 2.
The number of positive cells per glomerulus in the kidney was 0. Treatment with prednisolone reduced the PMN influx to 0. PMN infiltration quantification and stanning. In the case of the liver, the number of positive cells per microscopic field was 5. Treatment with prednisolone significantly diminished the PMN influx to 6. Relative expression of inflammatory genes. A Kidney samples. B Liver samples. In the kidney C3 expression was increased following BD and attenuated following prednisolone treatment.
While in the liver, C3 expression increased following BD and further increased due to prednisolone treatment Figure 5. In the kidney this ratio was increased following BD but decreased in the liver. Prednisolone treatment did not significantly modify this ratio under any experimental condition Figure 5. We studied the effects of the interventions on the relative expression of two cytoprotective genes.
The relative expression of Heme oxygenase 1 HO-1 in the kidney was up-regulated following BD and down-regulated following pre-treatment with prednisolone. In the liver the HO-1 expression was significantly up-regulated following prednisolone treatment.
However, the relative expression in the liver was significantly down-regulated due to prednisolone pre-treatment Figure 5. Disparity exists in the literature with regards to the beneficial effects of prednisolone administration to the donor on the outcomes of solid organ transplantation. Multiple large randomized control trials RCT have evaluated the effects on steroid administration on the outcomes of lung, kidney and liver transplant [ 35 — 37 ].
In a RCT, Bonser et al. Others in the realms of kidney transplantation have also failed to detect a significant improvement in the kidney survival at three months when 5g of methylprednisolone is administered to donors hours prior to explantation.
This dependency of the steroid concentrations on liver function was attributed to a decreased metabolic clearance and not to an increased systemic availability. Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding. Gut, 13 (), pp. This dependency of the steroid concentrations on liver function was attributed to a decreased metabolic clearance and not to an increased systemic availability. Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding. Gut, 13 (), pp. This study shows that prednisolone decreases inflammation and improves renal function, whilst not reducing liver injury. The persistence of. Borlak et al. Furthermore, case reports describing effects of corticosteroids in DILI were excluded. Reprints and Permissions. Acute liver toxicity due to methylprednisolone: consider this diagnosis in the context of autoimmunity. Not mentioned. Brain Behav.Federal government websites often end in. Before sharing sensitive information, make sure you're on a federal government site. The site is secure. NCBI Bookshelf. The corticosteroids are a group of chemically related natural hormones and synthetic agents that resemble the human adrenal hormone cortisol and have potent antiinflammatory and immunosuppressive properties and are widely used in medicine.
Corticosteroid therapy is associated with several forms of liver injury, some due to exacerbation of an underlying liver disease and some that appear to be caused directly by corticosteroid therapy. This discussion will cover eight agents: betamethasone, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, and triamcinolone.
Cortisol and the corticosteroids act by engagement of the intracellular glucocorticoid receptor, which then is translocated to the cell nucleus where the receptor-ligand complex binds to specific glucocorticoid-response elements on DNA, thus activating genes that mediate glucocorticoid responses.
The number of genes modulated by corticosteroids are many and the effects are multiple and interactive with other intracellular pathways. Thus, the effects of corticosteroids on inflammation and the immune system cannot be attributed to a single gene or pathway.
The potent antiinflammatory and immunosuppressive qualities of the corticosteroids have made them important agents in the therapy of many diseases.
Corticosteroids are available in multiple forms, including oral tablets and capsules; powders and solutions for parenteral administration; topical creams and lotions for skin disease; eye, ear and nose liquid drops for local application; aerosol solutions for inhalation and liquids or foams for rectal application.
Representative corticosteroids and the year of their approval for use in the United States include cortisone , prednisone , prednisolone , methylprednisolone , dexamethasone , betamethasone , and hydrocortisone All are available in generic forms.
In this website, only the oral and intravenous formulations of corticosteroids are described and they are discussed together with common list of references and representative case reports.
The corticosteroids are used widely in medicine largely for their potent antiinflammatory and immunosuppressive activities. Corticosteroids are used in several liver diseases, most commonly in autoimmune hepatitis for which they have been shown to improve outcome and survival.
Corticosteroids are also used after liver transplantation to prevent rejection. An important element in managing these liver diseases and conditions is to maintain the dose of corticosteroids at the lowest effective level.
The adverse effects of long term corticosteroid therapy which are rarely hepatic are still major causes of morbidity and even mortality in these conditions. Prednisone, prednisolone, methylprednisolone and triamcinolone are the most commonly used oral agents as they are inexpensive, rapid in onset, intermediate in duration of action and have potent glucocorticoid with minimal mineralocorticoid activities, at least as compared to cortisone and hydrocortisone.
Betamethasone and dexamethasone have greater glucocorticoid potency and less aldosterone-like activity than prednisone, but have a longer duration of action, and they are mostly used in topical or liquid forms for local application and in injectable forms for severe hypersensitivity reactions and inflammation. Methylprednisolone, dexamethasone, and hydrocortisone are most commonly used for intravenous administration, typically given in emergency or critical situations in which rapid and profound immunosuppression or antiinflammatory activity is needed.
The table below provides the major forms of corticosteroids and their relative glucocorticoid and mineralocorticoid activity and equivalent daily doses. View in own window. Cortisone kor' ti sone is a short acting glucocorticoid that is used for therapy of adrenal insufficiency and for treatment of allergic and inflammatory conditions. Cortisone is available in generic forms in tablets of 25 mg, which is considered a daily physiologic dose in adults.
Cortisone has both glucocorticoid and mineralocorticoid properties. Hydrocortisone hye" droe kor' ti sone is a rapid and short acting glucocorticoid that is used for therapy of adrenal insufficiency and in treatment of allergic and inflammatory conditions. Hydrocortisone has the same chemical structure as cortisol and thus most closely resembles the human adrenal hormone. Hydrocortisone is available in generic forms in tablets of 5, 10 and 20 mg, with 20 mg being considered a daily physiologic dose in adults.
Hydrocortisone is also available in multiple forms in solution for oral, rectal, topical or parenteral administration. A major use of intravenous hydrocortisone is in the acute therapy of severe hypersensitivity reactions and shock.
Hydrocortisone has both glucocorticoid and mineralocorticoid properties. Prednisone pred' ni sone is a synthetic, intermediate acting glucocorticoid that is widely used in the therapy of severe inflammation, autoimmune conditions, hypersensitivity reactions and organ rejection.
Prednisone is converted to prednisolone, its active form, in the liver. Prednisone is available in multiple generic forms in tablets of 1, 2. Four times more potent that cortisol, prednisone is used in varying doses, with 5 mg daily being considered physiologic doses in adults.
Prednisolone pred nis' oh lone is a synthetic, intermediate acting glucocorticoid that is widely used in the therapy of severe inflammation, autoimmune conditions, hypersensitivity reactions and organ rejection. Prednisolone is available in multiple generic forms in tablets of 5, 10, 15 and 30 mg and in several forms for systemic administration. Four times more potent that cortisol, prednisolone is used in varying doses, with 5 mg daily being considered physiologic doses in adults.
Methylprednisolone meth" il pred nis' oh lone is a synthetic, intermediate acting glucocorticoid that is widely used in the therapy of severe inflammation, autoimmune conditions, hypersensitivity reactions and organ rejection. Methylprednisolone is available in multiple forms in tablets of 2, 4, 8, 16 and 32 mg generically and under the brand name of Medrol and in Medrol Dosepaks 21 tablets of 4 mg each.
Injectable forms of methylprednisolone are also available generically and under brand names of Solu-Medrol and Depo-Medrol. Five times more potent that cortisol, methylprednisolone is used in varying doses, with 4 mg daily being considered physiologic doses in adults.
Methylprednisolone has minimal mineralocorticoid activity. Triamcinolone trye" am sin' oh lone is a synthetic, long acting glucocorticoid that is used in topical solutions and aerosols for therapy of allergic and hypersensitivity reactions and control of inflammation as well as in parenteral formulations for therapy of hypersensitivity reactions, shock and severe inflammation.
Oral forms of triamcinolone include tablets of 4 and 8 mg and oral syrups. Parenteral forms for injection are available under various generic and trade names including Aristocort and Kenacort. Triamcinolone is five times more potent than cortisol in its glucocorticoid activity, but has minimal mineralocorticoid activity. Dexamethasone dex" a meth' a sone is a synthetic, long acting glucocorticoid that is used parenterally as therapy of severe hypersensitivity reactions, shock and control of severe inflammation as well as in topical, otic, ophthalmologic solutions, aerosols and lotions or creams for local therapy of allergic reactions and inflammation.
Most recently, intravenous dexamethasone has been found to be beneficial in severe COVID pneumonia with respiratory failure in patients requiring high flow oxygen supplementation or invasive mechanical ventilation.
Dexamethasone is available in multiple forms for injection under various generic and trade names including Decadron. Dexamethasone is 25 times more potent than cortisol in its glucocorticoid activity, but has minimal mineralocorticoid activity.
Betamethasone bay" ta meth' a sone is a synthetic, long acting glucocorticoid that is used in parenteral forms for therapy of allergic and hypersensitivity reactions and control of severe inflammation.
Betamethasone is available in solution for injection under the trade name of Celestone and in multiple generic forms as syrups and effervescent tablets for oral use, edemas and foams for rectal use, aerosols for nasal and respiratory use, and creams and lotions for topical use. Betamethasone is 25 times more potent than cortisol in glucocorticoid activity, but has minimal mineralocorticoid activity.
Corticosteroids have multiple adverse side effects, due to their multiplicity of actions affecting virtually all organs. Long term use has very profound effects on growth and can lead to cataracts, glaucoma, opportunistic infections, thinning of the skin, weight gain and redistribution of fat, insulin resistance and diabetes, hypertension, headache, psychiatric problems, sodium retention and peripheral edema; all of the clinical features of Cushing syndrome. Corticosteroids also have major effects on the liver, particularly when given long term and in higher than physiologic doses.
Glucocorticoid use can result in hepatic enlargement and steatosis or glycogenosis. Corticosteroids can trigger or worsen nonalcoholic steatohepatitis. Long term use can also exacerbate chronic viral hepatitis. Importantly, treatment with corticosteroids followed by withdrawal or pulse therapy can cause reactivation of hepatitis B and worsening or de novo induction of autoimmune hepatitis, both of which can be fatal.
Finally, high doses of intravenous corticosteroids, largely methylprednisolone, have been associated with acute liver injury which can result in acute liver failure and death. Thus, the hepatic complications of corticosteroids are mostly associated with high intravenous dosing usually represent the worsening or triggering of an underlying liver disease and rarely are the result of drug hepatotoxicity.
Corticosteroid therapy can cause hepatic steatosis and hepatic enlargement, but this is often not clinically apparent, particularly in adults. This effect can occur quite rapidly and is rapidly reversed with discontinuation.
High doses and long term use has been associated with the development or exacerbation of nonalcoholic steatohepatitis with elevations in serum aminotransferase levels and liver histology resembling alcoholic hepatitis with steatosis, chronic inflammation, centrolobular ballooning degeneration and Mallory bodies Case 1.
However, symptomatic or progressive liver injury from corticosteroid induced steatohepatitis is uncommon. Furthermore, corticosteroids may act to worsen an underlying nonalcoholic fatty liver disease rather than causing the condition de novo. The worsening may be due to direct effects of glucocorticoids on insulin resistance or fatty acid metabolism or may be the result of weight gain which is common with long term corticosteroid therapy. While simple steatosis induced by corticosteroids is rapidly reversible, steatohepatitis can be slow to resolve upon withdrawal of corticosteroids.
Corticosteroids in high doses can also cause hepatic glycogenosis, in which liver cells exhibit a homogenous appearance and stain strongly for glycogen using PAS staining with and without diastase. Glycogenosis can also be associated with hepatomegaly in children and elevations in serum aminotransferase levels with minimal or no change in alkaline phosphatase or bilirubin levels. Glycogenosis is usually asymptomatic and does not appear to progress to chronic liver injury, cirrhosis or acute liver failure.
While glycogenosis has been described largely in patients with poorly controlled type 1 diabetes, it also can occur acutely in patients started on high dose corticosteroids. An important complication of corticosteroid therapy is the worsening of an underlying chronic viral hepatitis. In chronic hepatitis B, corticosteroids can induce increases in viral replication and serum hepatitis B virus HBV DNA levels while decreasing serum aminotransferase levels.
Eventually, however, the increase in viral replication can worsen the underlying liver disease. Exacerbation of hepatitis becomes particularly evident when corticosteroids are withdrawn or lowered to physiological levels. As the immune system recovers, hepatitis worsens and serum aminotransferase levels can rise to greater than to fold elevated usually accompanied by a prompt decrease in HBV DNA levels. This flare of disease following withdrawal of corticosteroids can be severe and result in acute liver failure or significant worsening of chronic hepatitis and development of cirrhosis Case 2.
Reactivation of hepatitis B can be prevented by prophylactic use of antiviral therapy during the period of immunosuppression, but even this may not prevent some degree of liver injury.
Corticosteroids also appear to worsen the course of chronic hepatitis C, although in a less dramatic fashion than in chronic hepatitis B. Corticosteroid therapy leads to a rise in hepatitis C virus HCV RNA levels which may eventually cause worsening of the underlying liver disease. Chronic hepatitis C appears to be more severe and is particularly difficult to manage in patients receiving chemotherapy or immunosuppression, and corticosteroids are believed to be a major factor in this effect.
Thus, corticosteroids should be avoided if possible in patients with underlying chronic viral hepatitis. Corticosteroids are used in the therapy of autoimmune hepatitis and, therefore, are likely to be beneficial rather than harmful in patients with this disease. The difficulty arises when corticosteroids are stopped, which can cause a rebound exacerbation of the autoimmune hepatitis that is often severe and can be fatal.
Importantly, there have been multiple reported instances of de novo appearance of severe autoimmune hepatitis in patients who received a short course or pulse of corticosteroids for another, unrelated condition such as asthma or allergic reactions. In these situations, a mild and subclinical autoimmune hepatitis was likely present before corticosteroids were started, and the suppression of the disease followed by immune rebound caused the clinical presentation of the condition. These patients generally respond to restarting corticosteroids, but may require long term if not lifelong immunosuppressive treatment thereafter.
Finally, there have been several reports of an acute hepatitis-like liver injury arising after a short, high dose course of intravenous methylprednisolone that can be severe and even fatal, and in which viral hepatitis and autoimmune hepatitis cannot be clearly implicated Case 3.
The cause of this apparent hepatotoxicity is not known, but it may represent severe autoimmune hepatitis triggered by the sudden profound immunosuppression and subsequent immune reconstitution. Importantly, symptoms and jaundice develop 1 to 6 weeks after stopping methylprednisolone and the pattern of serum enzyme elevations is typically hepatocellular. These episodes can be symptomatic and severe. Immunoallergic manifestations are uncommon and autoantibodies may not be present.
Several instances have resulted in acute liver failure resulting in death or need for emergency liver transplantation.
Comments
Post a Comment