Hepatotoxicity following cyclophosphamide treatment in a patient with MPO-ANCA vasculitis
Hepatotoxicidad tras tratamiento con ciclofosfamida en un paciente con vasculitis MPO-ANCA
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"apellidos" => "Amorós" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Medicina Interna, Complejo Hospitalario La Mancha-Centro, Alcázar de San Juan, Ciudad Real, " "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "affa" ] 1 => array:3 [ "entidad" => "Sección de Nefrología, Hospital General de Elche, Elche, Alicante, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 2 => array:3 [ "entidad" => "Servicio de Digestivo, Hospital General de Elche, Elche, Alicante, " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hepatotoxicidad tras tratamiento con ciclofosfamida en un paciente con vasculitis MPO-ANCA" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10917_108_19860_en_10917_f1.jpg" "Alto" => 282 "Ancho" => 600 "Tamanyo" => 80309 ] ] "descripcion" => array:1 [ "en" => "Evolution of GOT, GPT and GGT during cyclophosphamide treatment" ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">To the Editor, </span></p><p class="elsevierStylePara">Cyclophosphamide is a synthetic alkylating agent used in chemotherapy and as an immunosuppressive agent. Among its adverse effects are infections, myelosuppression, haemorrhagic cystitis, hypersensitivity reactions, digestive/hepatic, pulmonary, cardiac and neurological toxicity, sterility and syndrome of inappropriate antidiuretic hormone hypersecretion (SIADH).<span class="elsevierStyleSup">1-3</span></p><p class="elsevierStylePara">We describe a patient with abdominal pain and an increase in hepatic and pancreatic enzymes after cyclophosphamide administration.</p><p class="elsevierStylePara">Male, 57-year-old patient, admitted for renal failure. Patient history: arthralgia and arthritis during the past 10 years, deafness, frequent nosebleeds; pancreatitis due to cholelithiasis a month before. Physical examination: he did not have fever, blood pressure: 130/70mm Hg; lung crackles in both lungs, and remaining data were normal. The analysis showed: haemoglobin: 8.1g/dl: (13-17); creatinine: 6.44mg/dl (0.84-1.25); urea: 163mg/dl (17-43); albumin: 2.63g/dl (3.50-5.20); GOT: 5IU/l (10-39); GPT: 15IU/l (10-45); GGT: 71IU/l (10-55); alkaline phosphatase: 102IU/l (30-120); total bilirubin: 0.69mg/dl (0.3-1.2); amylase: 100IU/l (22-80); sediment: 60-100 red blood cells per field; proteinuria: 1.5g/24hr; negative urine culture. Negative c-ANCA, positive p-ANCA, negative PR3, MPO: 50.5(N<7IU/ml); negative anti-MBG antibodies, negative serology tests for hepatitis B, C and human immunodeficiency virus (HIV). Abdominal ultrasound: cholelithiasis, normal-size kidneys; pulmonary computerised tomography (CT) revealed bilateral nodes. The kidney biopsy showed focal and segmental necrotising glomerulonephritis with few deposits seen in the immunofluorescence. The patient was diagnosed with ANCA-positive vasculitis (microscopic polyangiitis/Wegener’s granulomatosis).</p><p class="elsevierStylePara">He was treated with three 500-mg boli of methylprednisolone, continuing with 60mg of prednisone a day orally, haemodialysis and plasmapheresis. He also received omeprazole, calcium carbonate, sevelamer, furosemide and erythropoietin. The first cyclophosphamide bolus was administered (500mg) and 12 hours later the patient presented with sweating and diffuse abdominal pain, with no signs of peritoneal irritation. He presented with GOT: 90IU/l; GPT: 76IU/l; GGT: 645IU/l; alkaline phosphatase: 109IU/l; total bilirubin: 0.66mg/dl and amylase: 173IU/l. These parameters normalised in the following days. Fifteen days later the second cyclophosphamide bolus was prescribed (750mg), and 24 hours later the pain in the right hypochondrium reappeared. He presented with GOT: 144IU/l; GPT: 358IU/l; GGT: 802IU/l; alkaline phosphatase: 103IU/l; total bilirubin: 6.44mg/dl; amylase: 208IU/l; lipase: 378IU/l (21-67); which decreased in the following days. The magnetic resonance cholangiography showed cholelithiasis with no signs of complications, bile duct not dilated, free of choledocholithiasis. After 15 days he was administered 50mg/day of oral cyclophosphamide. After 4 days he presented with self-limited pain in the right hypochondrium. He had GOT: 27IU/l; GPT: 281IU/l; GGT: 871IU/l; alkaline phosphatase: 129IU/l; total bilirubin: 0.74mg/dl; amylase 97IU/l and lipase 154IU/l (Figure 1). Cyclophosphamide was withdrawn and treatment with mycophenolate mofetil was started at a dose of 500mg/8 hours. After a month, the patient was asymptomatic, normotensive, with spontaneous diuresis of 2l/day, Cr 2.59mg/dl; GPT: 9IU/l; GPT: 28IU/l; GGT: 155IU/l; alkaline phosphatase: 105IU/l; total bilirubin: 0.68mg/dl; normal amylase and lipase, weakly positive MPO-ANCA. The lung computerised tomography (CT) showed that the images had almost disappeared.</p><p class="elsevierStylePara">The effectiveness and toxicity of cyclophosphamide differs greatly from one patient to another, which has mainly been related to pharmacokinetic and pharmacogenetic mechanisms.<span class="elsevierStyleSup">1,2,4,5</span> As such, Navin Pinto et al suggest that certain polymorphisms of enzymes metabolising cyclophosphamide (cytochrome P450, glutathione <span class="elsevierStyleItalic">S</span>-transferases and aldehyde-dehydrogenases) could be related to this variation.<span class="elsevierStyleSup">3</span> A relationship has been found between high doses of cyclophosphamide and its toxic metabolites (acrolein and phosphoramide mustard) and hepatotoxicity.<span class="elsevierStyleSup">2,4</span> Hepatotoxicity has also been related to high levels of other metabolites such as 4-hydroxycyclophosphamide<span class="elsevierStyleSup">2 </span>and <span class="elsevierStyleItalic">o</span>-carboxyethyl-phosphoramide mustard.<span class="elsevierStyleSup">4</span> Furthermore, it has been shown that cyclophosphamide-induced adverse reactions could be due to cholinesterase inhibition.<span class="elsevierStyleSup">6</span> Cyclophosphamide-induced hepatotoxicity is characterised by cytolysis and cholestasis, as occurred in this case. It may appear with oral or intravenous administration and seems to depend on the dosage. Three histological patterns have been described: massive hepatic necrosis, necrosis of perivenous hepatocytes and diffuse hepatocellular damage with mild steatosis.<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Patients with advanced renal failure can have high levels of amylase (up to three times the upper normal limit) and lipase (up to double). In this patient, after the second cyclophosphamide bolus, an increase in lipase, five times the normal level was observed, which may indicate pancreatic involvement. As far as we are aware, cyclophosphamide is not associated with pancreatitis, but iphosphamide, another nitrogen mustard, similar to cyclophosphamide is described to produce pancreatitis.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">ANCA vasculitis can affect the digestive system. Our patient’s cholelithiasis was not complicated; biliary colic could cause analytical alterations similar to those that developed, but in the magnetic resonance cholangiography there were no signs of choledocholithiasis. In this case, there was a clear temporary relationship with cyclophosphamide, which supports the drug’s role. According to Naranjo et al’s<span class="elsevierStyleSup">8</span> scale, hepatotoxicity and cyclophosphamide are likely to be related in this case.</p><p class="elsevierStylePara">This case shows that hepatic and pancreatic functions must be monitored during treatment.</p><p class="elsevierStylePara"><a href="grande/10917_108_19860_en_10917_f1.jpg" class="elsevierStyleCrossRefs"><img src="10917_108_19860_en_10917_f1.jpg" alt="Evolution of GOT, GPT and GGT during cyclophosphamide treatment"></img></a></p><p class="elsevierStylePara">Figure 1. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 8 | 16 |
| 2024 October | 89 | 41 | 130 |
| 2024 September | 124 | 30 | 154 |
| 2024 August | 108 | 59 | 167 |
| 2024 July | 104 | 33 | 137 |
| 2024 June | 118 | 42 | 160 |
| 2024 May | 100 | 51 | 151 |
| 2024 April | 69 | 41 | 110 |
| 2024 March | 53 | 29 | 82 |
| 2024 February | 76 | 38 | 114 |
| 2024 January | 52 | 35 | 87 |
| 2023 December | 76 | 46 | 122 |
| 2023 November | 94 | 48 | 142 |
| 2023 October | 112 | 63 | 175 |
| 2023 September | 140 | 48 | 188 |
| 2023 August | 103 | 34 | 137 |
| 2023 July | 97 | 42 | 139 |
| 2023 June | 109 | 25 | 134 |
| 2023 May | 100 | 45 | 145 |
| 2023 April | 93 | 24 | 117 |
| 2023 March | 132 | 24 | 156 |
| 2023 February | 79 | 32 | 111 |
| 2023 January | 82 | 30 | 112 |
| 2022 December | 74 | 37 | 111 |
| 2022 November | 71 | 37 | 108 |
| 2022 October | 82 | 77 | 159 |
| 2022 September | 63 | 48 | 111 |
| 2022 August | 77 | 51 | 128 |
| 2022 July | 55 | 48 | 103 |
| 2022 June | 66 | 40 | 106 |
| 2022 May | 48 | 34 | 82 |
| 2022 April | 83 | 67 | 150 |
| 2022 March | 81 | 50 | 131 |
| 2022 February | 104 | 44 | 148 |
| 2022 January | 99 | 45 | 144 |
| 2021 December | 141 | 48 | 189 |
| 2021 November | 70 | 44 | 114 |
| 2021 October | 165 | 37 | 202 |
| 2021 September | 93 | 54 | 147 |
| 2021 August | 98 | 44 | 142 |
| 2021 July | 66 | 36 | 102 |
| 2021 June | 59 | 42 | 101 |
| 2021 May | 62 | 45 | 107 |
| 2021 April | 152 | 79 | 231 |
| 2021 March | 105 | 53 | 158 |
| 2021 February | 108 | 17 | 125 |
| 2021 January | 74 | 24 | 98 |
| 2020 December | 60 | 29 | 89 |
| 2020 November | 57 | 15 | 72 |
| 2020 October | 57 | 24 | 81 |
| 2020 September | 56 | 12 | 68 |
| 2020 August | 79 | 12 | 91 |
| 2020 July | 77 | 18 | 95 |
| 2020 June | 66 | 16 | 82 |
| 2020 May | 69 | 15 | 84 |
| 2020 April | 56 | 31 | 87 |
| 2020 March | 57 | 16 | 73 |
| 2020 February | 71 | 38 | 109 |
| 2020 January | 87 | 35 | 122 |
| 2019 December | 98 | 23 | 121 |
| 2019 November | 91 | 35 | 126 |
| 2019 October | 46 | 11 | 57 |
| 2019 September | 77 | 27 | 104 |
| 2019 August | 41 | 11 | 52 |
| 2019 July | 47 | 24 | 71 |
| 2019 June | 36 | 11 | 47 |
| 2019 May | 56 | 19 | 75 |
| 2019 April | 102 | 35 | 137 |
| 2019 March | 53 | 22 | 75 |
| 2019 February | 23 | 14 | 37 |
| 2019 January | 68 | 29 | 97 |
| 2018 December | 115 | 57 | 172 |
| 2018 November | 160 | 16 | 176 |
| 2018 October | 151 | 16 | 167 |
| 2018 September | 102 | 11 | 113 |
| 2018 August | 108 | 18 | 126 |
| 2018 July | 78 | 19 | 97 |
| 2018 June | 82 | 8 | 90 |
| 2018 May | 88 | 17 | 105 |
| 2018 April | 90 | 10 | 100 |
| 2018 March | 67 | 10 | 77 |
| 2018 February | 90 | 12 | 102 |
| 2018 January | 70 | 9 | 79 |
| 2017 December | 77 | 10 | 87 |
| 2017 November | 46 | 10 | 56 |
| 2017 October | 29 | 9 | 38 |
| 2017 September | 43 | 9 | 52 |
| 2017 August | 49 | 20 | 69 |
| 2017 July | 41 | 11 | 52 |
| 2017 June | 45 | 10 | 55 |
| 2017 May | 59 | 15 | 74 |
| 2017 April | 47 | 20 | 67 |
| 2017 March | 37 | 10 | 47 |
| 2017 February | 42 | 10 | 52 |
| 2017 January | 35 | 10 | 45 |
| 2016 December | 49 | 5 | 54 |
| 2016 November | 58 | 12 | 70 |
| 2016 October | 93 | 11 | 104 |
| 2016 September | 124 | 5 | 129 |
| 2016 August | 186 | 10 | 196 |
| 2016 July | 121 | 14 | 135 |
| 2016 June | 125 | 0 | 125 |
| 2016 May | 132 | 0 | 132 |
| 2016 April | 120 | 0 | 120 |
| 2016 March | 87 | 0 | 87 |
| 2016 February | 109 | 0 | 109 |
| 2016 January | 102 | 0 | 102 |
| 2015 December | 125 | 0 | 125 |
| 2015 November | 92 | 0 | 92 |
| 2015 October | 88 | 0 | 88 |
| 2015 September | 70 | 0 | 70 |
| 2015 August | 75 | 0 | 75 |
| 2015 July | 86 | 0 | 86 |
| 2015 June | 42 | 0 | 42 |
| 2015 May | 57 | 0 | 57 |
| 2015 April | 16 | 0 | 16 |
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