Table 1.
Summarized demographic and clinical information of methylprednisolone-induced liver injury events reviewed in literature (n=50).
| Case no.- author | Age (yr)/ sex (M/F) | Indication for MP treatment | Cumulative MP dosage g; (treatment duration, d) | Time to onset, wksa | Concomitant medication | Clinical presentation | Time to resolution, wksa | Liver biopsy | Outcome | Re- challenge, (n) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1.-Davidov et al. | 23/F | MS | 3 (3) | 3 | - | Jaundice, fever, nausea, vomiting | 12 | Hepatocyte dropouts in central areas, congestion and chronic inflammation; portal tracts enlarged due to chronic inflammation (lymphocytes, eosinophils and plasma cells); in parenchyma, acidophilic bodies accompanied by inflammatory cells; hepatocytes showed signs of regeneration | R | Yes (1) |
| 2.-Moleti et al. (1) | 58/M | GO | 3.2 (84) | 5 | - | Asymptomatic | 6 | - | R | - |
| 3.-Moleti et al. (2) | 50/F | GO | 1.5 (84) + oral prednisone during interpulse periods | 3 | Methimazole | Asymptomatic | 16 | - | R | - |
| 4.-Grilli et al. | 35/F | MS | 5 (5) | 4 | - | Jaundice | 4 | Nodular parenchyma partially surrounded by fibrotic septa emerging from portal tracts; moderately dense inflammatory infiltrate (lymphocytes, plasma cells, eosinophils and neutrophils); bridging and confluent necrosis | R | Yes (1) |
| 5.-Ferraro et al. (1) | 50/F | MS | 1 (5) | 1 | Lisinopril | N/A | 4 | - | R | - |
| 6.-Ferraro et al. (2) | 30/F | MS | 1 (5) | 1 | - | N/A | 2 | - | R | - |
| 7.-Ferraro et al. (3) | 38/F | MS AITD | 1 (5) | 8 | - | N/A | 4 | Inflammatory infiltrate, patched focal necrosis, periportal fibrosis and numerous ceroid-laden macrophages | R | - |
| 8.-Ferraro (4) et al. | 24/F | MS | 1 (5) + 1-mo taper | 16 | - | N/A | 16 | Inflammatory infiltrate, patched focal necrosis, periportal fibrosis and numerous ceroid-laden macrophages | R | Yes (3) |
| 9.-Oliveira et al. | 33/F | MS | 1 (N/A) + oral maintenance | N/A | Cyclophospha-mide, glatiramer acetate | Jaundice | N/A | Severe interface hepatitis and centrilobular hepatocyte necrosis with mild fibrotic changes | R | Yes (4) |
| 10.-Melamud et al. | 52/M | GO | 0.5 (14) | 2 | Atorvastatin, ciprofibrate, levothyroxine | Jaundice, weakness, arthralgia | 28 | - | R | Yes (1) |
| 11.-D'Agnolo et al. | 48/F | MS | 1 (3) | 3 | - | Abdominal pain, nausea | N/A | - | R | Yes (1) |
| 12.-Carrier et al. | 30/F | MS | 1 (N/A) | 2 | APAP (levels below toxic doses) | Jaundice, asthenia | N/A | Significant bridging necrosis between central veins and portal tracts/ portal spaces; in necrotic foci, inflammatory lymphocytic infiltrate with plasma cells eosinophils; intrahepatocytic cholestasis | R | Yes (2) |
| 13.-Alva et al. | 38/F | ILD | 0.96b (30) | N/A | N/A | Jaundice, rash, pruritus | 24 | Cholestatic hepatitis with early stage fibrosis | R | - |
| 14.-Furutama et al. | 11/F | MS | 3 (3) | 6 | - | Febricula, fatigue | 2 | - | R | Yes (2) |
| 15.-Gutkowski et al. | 24/F | MS | 3 (N/A) | 4 | IFN-β (2 ij) + APAP (single dose at each ij) | Jaundice | 3 | - | R | Yes (1) |
| 16.-Loraschi et al. (1) | 33/M | DE | 2.5 (4) | 5 | - | Asymptomatic | 3 | Focal necrosis (acinar zones II and III), monocyte/macrophage infiltration, Kupffer cell hyperplasia, acidophilic bodies and focal microvesicular steatosis | R | - |
| 17.-Loraschi et al. (2) | 27/F | RBON | 4.5 (6) | 1 | - | Asymptomatic | 1 | - | R | - |
| 18.-Maámouri et al. | 37/F | MS | 3 (3) | 3 | - | Asymptomatic | N/A | Lymphoplasmacytic portal inflammatory infiltrate with interphase hepatitis and bridging fibrosis | R | - |
| 19.-Rivero et al. | 57/F | MS | 3 (3) | 1 | - | Asymptomatic | 12 | Lytic necrosis and macrophage hyperplasia with ceroid-laden macrophages | R | Yes (2) |
| 20.-Takahashi et al. | 43/F | MS | 3 (3) | 4 | IFN-β | Nausea, vomiting | N/A | Perivenular bridging necrosis with inflammatory infiltration including eosinophils and interphase hepatitis | R | Yes (1) |
| 21.-Reuß et al. | 42/F | MS | 5 (N/A) | 3 | - | Asymptomatic | N/A | Active hepatitis with portal lymphocyte infiltration and fibrosis | - | - |
| 22.-Topal et al. | 47/F | CNSV, self- medication | 0.224/db (7) | 1 | Topiramate | Jaundice, weakness, anorexia,nausea, pruritus, acholia, choluria | 7 | - | R | - |
| 23.-Das et al. | 48/F | MS | N/A | 6 | - | Jaundice, nausea, vomiting | N/A | Infiltrate with lymphocytes, eosinophils and plasmatic cells; more apparent in perivenular acinar region III; increasing presence of councilman bodies | R | Yes (1) |
| 24.-Hofstee et al. | 46/F | MS | 1 (3) | 6 | - | Asymptomatic | 16 | - | R | Yes (2) |
| 25.-Marinó et al. | 43/F | GO | 4.7 (N/A) | 6 | - | Asymptomatic | 9 | Lymphoplasmacytic infiltrate affecting interlobular bile conducts; focal centrilobular necrosis | R | - |
| 26.-Marinó et al. (1) | 56/N/A | GO | 15 (56) | 8 | Oestrogens | Jaundice, fatigue, anorexia, diarrhoea | 7ß | Massive necrosis | Exitus | - |
| 27.-Marinó et al. (2) | 63/N/A | GO | 9.3 (49) | 8 | Atenolol, propafenone, quinapril | Jaundice, fatigue, anorexia, diarrhoea | 7ß | N/A | Exitus | - |
| 28.-Marinó et al. (3) | 47/N/A | GO | 8.3 (35) | 18 | - | Jaundice, fatigue, anorexia, diarrhoea | 5ß | N/A | Exitus (post- LTX) | - |
| 29.-Marinó et al. (4) | 45/N/A | GO | 9.3 (49) | 15 | Ciprofloxacin | Asymptomatic | 23 | Moderate necrosis | R | - |
| 30.-Marinó et al. (5) | 30/N/A | GO | 7.2 (35) | 18 | - | Asymptomatic | 18 | Lobular and portal lymphocytic infiltrate with eosinophilia | R | - |
| 31.-Marinó et al. (6) | 55/N/A | GO | 10.7 (35) | 16 | Trandolapril | Asymptomatic | 9 | N/A | R | - |
| 32.-Marinó et al. (7) | 54/N/A | GO | 4 (21) | 4 | Oestrogens | Asymptomatic | 20 | Confluent necrosis; lymphocytic and plasma cell infiltrates | R | - |
| 33.-Salvi et al. | 43/F | HT | 5.5 (136) | 8 | N/A | Asymptomatic | 18 | Lobular hepatitis with central necrosis, presence of lymphocytes and plasma cell infiltrates, acidophilic bodies and Kupffer cell hyperplasia | R | - |
| 34.-Weissel et al. | 71/F | GO | 15 (N/A) | 4 | Methimazole, cortisone | N/A | 2ß | Necrosis of liver parenchyma | Exitus | - |
| 35-Dumontier et al. (1) | 40/F | Alopecia Areata | N/A | 7 | N/A | N/A | 30 | - | R | - |
| 36-Dumontier et al. (2) | 26/F | MS | N/A | 11 | N/A | N/A | 4 | Portal fibrosis, no signs of autoimmune hepatitis, cholestasis or steatosis (performed 2 months after the second episode) | R | Yes (2) |
| 37-Dumontier et al. (3) | 27/F | MS | N/A | 9 | N/A | N/A | 11 | Focal liver cell necrosis in acinar zone 3 | R | Yes (1) |
| 38-Dumontier et al. (4) | 36/M | Alopecia Areata | N/A | 5 | N/A | N/A | 7 | Central lobular necrosis (30% of liver parenchyma) | R | - |
| 39-Dumontier et al. (5) | 27/F | MS | N/A | 4 | Teriflunomide | Mild asthenia | 154 | Central lobular necrosis | R | Yes (2) |
| 40.-Hidalgo et al. (1) | 28/F | MS | 1.5 (9) | 7 | - | Jaundice, choluria, acholia, nausea, vomiting | 4 | Lymphocyte-oedematous background and fibrotic changes related to mild chronic hepatitis | R | Yes (1) |
| 41.-Hidalgo et al. (2) | 37/M | Transverse myelitis | 1 (5) | 6 | - | Asymptomatic | N/A | No inflammatory changes (biopsy performed 2 months after episode) | R | - |
| 42.-Hidalgo et al. (3) | 35/F | MS | 1 (5) | 1 | - | Asymptomatic | N/A | - | R | - |
| 43.-Abramavicius et al. | 74/F | GO | 4 (57) | 5 | Methimazole | Asymptomatic | N/A | - | R | - |
| 44.-Lee et al. | 34/M | MS | 1 (5) + 1/mo maintenance dose | 20 | - | Asymptomatic | 30 | Centrilobular necrosis | R | - |
| 45.-Kadle et al. | 51/F | AITD, MS | 0.5 (10) | 7 | - | Weakness, anorexia, weight loss, jaundice | 22 | - | R | - |
| 46.-Adamec et al. (1) | 37/F | MS | 3 (3) | 4 | IFN-β | Nausea, epigastric pain | N/A | Centrilobular necrosis with lymphocytic and eosinophilic infiltrates | R | Yes (1) |
| 47.-Adamec et al. (2) | 46/F | MS | 3 (3) | 4 | Vitamin D | Asymptomatic | N/A | Mild diffuse hepatic steatosis | R | Yes (1) |
| 48.-Adamec et al. (3) | 44/F | MS | 3 (3) | 12 | - | Jaundice, nausea, anorexia | N/A | Portoportal and portocentral necrosis with lymphocytic infiltrate | R | - |
| 49.-Bresteau et al. | 35/F | MS | 5 (5) | 8 | - | Asymptomatic | 6 | Confluent necrosis, severer at terminal hepatic venule, portal tract inflammation, no bile duct damage | R | - |
| 50.-Rotondo et al. | 16/F | MS | 5 (5) | 4 | - | Urticaria, angioedema, nausea, vomiting | 8 | Focal centrilobular hepatocyte necrosis with interface hepatitis | R | - |
| Our cases | ||||||||||
| Patient 1 | 31/F | MS | 0.9 (3) | 2 | IFN-β, glatiramer acetate | Jaundice, weakness, nausea | N/A | Acute hepatitis, portal fibrosis and mixed infiltration including eosinophils; centrizonal necrosis | N/A | - |
| Patient 2 | 36/F | MS | 3 (3) + 60 mg/day p.o. (21 days) | 2 | IFN-β, sertraline | Asymptomatic | 12 | - | R | Yes (3) |
| Patient 3 | 33/F | MS | 7 (7) + prednisone p.o. (12 days) | 6 | - | Jaundice, intermittent pruritus | N/A | Minimal residual hepatitis without fibrosis | R | Yes (1) |
Summarized demographic, clinical, histological and laboratory data correlated with a first exposure of methylprednisolone (in case accidental rechallenge applied) or with the episode described in the manuscript and/or displaying enough information.
a
Time units were registered as weeks, and when days were indicated in the original publication, they were rounded up (e.g., 1–7 days equals 1 week; 8–14 days equals 2 weeks, etc.).
b
MP was administered exclusively p.o. in contrast to the rest of the cases where MP was administered intravenously only.
Abbreviations: MP: methylprednisolone; M: male; F: female; y: years; N/A: not available; mo: month; wk: weeks; d: days; g: gram; MS: multiple sclerosis; GO: Graves' ophthalmopathy; AITD: autoimmune thyroid diseases; IFN-β: interferon beta; ILD: interstitial lung disease; DE: demyelinating encephalopathy; CNSV: central nervous system vasculitis; RBON: retrobulbar optic neuritis; post-LTX: after liver transplantation; HT: Hashimoto's thyroiditis; EP: enoxiparin; CaC: calcium carbonate; CaG: calcium gluconate; PP: pantoprazole; MMZ: metamizole; APAP: acetaminophen; AV: Aloe vera; ij: injections; R: recovery; ß: time to exitus.