Iron and acetaminophen a fatal combination?

Transplant International ISSN 0934-0874 Iron and acetaminophen a fatal combination?Vinod K. Audimoolam, Julia Wendon, William Bernal, Nigel Heaton, John O'Gradyand Georg Auzinger Institute of Liver Studies, King's College Hospital, London, UK acute liver failure, fungal sepsis, ironpoisoning, liver transplantation.
Intentional iron overdose in adults is uncommon. Clinical consequences arevariable and depend on the quantity of iron ingested and the delay to treat- ment. Severe iron overdose can lead to multi-organ failure and acute hepatic Dr Georg Auzinger, Institute of Liver Studies, necrosis. Here, we report three cases of polypharmacy overdose including iron King's College Hospital, Denmark Hill, London, resulting in acute liver failure. Despite maximum supportive care including SE 5 9 RS, UK. Tel.: 00442032993367; fax: liver transplantation in two cases, all patients died. Iron poisoning may have 00442032993899; e-mail: an additive toxic effect in drug-induced acute liver failure and worsen out-come.
Conflicts of InterestNo conflict of interest Received: 7 April 2011Revision requested: 9 May 2011Accepted: 1 August 2011Published online: 30 August 2011 Accidental iron toxicity is not uncommon in the paediat- An 18-year-old woman was admitted to her referring hos- ric setting, whereas among adults iron ingestion in the pital having ingested approximately 60 mg of diazepam, majority is with suicidal intent and is rarely seen. The 600 mg of diclofenac and ferrous sulphate, possible more incidence of iron poisoning among children <5 years of than 6 g, 24–48 h prior to admission. Her admission liver age has been reported to be as high as 30%; however, this function tests were compatible with a diagnosis of hyper number seems to be in decline following the introduction acute hepatic necrosis [aspartate transaminase (AST) of unit dose packaging of iron supplements [1–3]. In its 13374 IU/L, prothrombin time (PT) 90 s, lactate (lac) most severe form, iron toxicity can lead to acute liver and 18 mmol/L] and she was clinically encephalopathic.
multi-organ failure. Initial treatment includes gut decon- Admission and pre- transplantation iron serum levels tamination, chelation therapy with desferrioxamine and were 67 mmol/L (374 lg/dL) and 34.6 mmol/L (193 lg/ organ supportive measures [4]. Liver transplantation in dL) respectively (normal range 14–30 mmol/L). She was patients presenting with acute liver failure (ALF) is a commenced on intravenous N-acetylcysteine and desferri- treatment option but conclusive evidence regarding its efficacy is lacking. Here we present three cases of ALF Within the first 24 h following transfer, she developed resulting from acetaminophen and diclofenac overdose acute respiratory distress syndrome, P/F < 100 mmHg and vasoplegic shock. Desferrioxamine was discontinued patients fulfilled transplant criteria for ALF and two were given concerns regarding respiratory toxicity [5]. Trans- transplanted, none survived. We postulate that iron poi- thoracic echocardiogram revealed right heart dysfunction soning had a significant impact on the ultimately fatal and pulmonary hypertension. Over the next 12 h both disease course of these patients.
ª 2011 The AuthorsTransplant International ª 2011 European Society for Organ Transplantation 24 (2011) e85–e88 Iron and acetaminophen combination Audimoolam et al.
decreased significantly with aggressive multi organ sup- Her clinical condition continued to deteriorate finally port. An intracranial pressure (ICP) monitoring device progressing to brain stem death approximately 12 weeks was inserted (right fronto-parietal region) and the open- after her initial admission.
ing ICP measured 28 mmHg; Intracranial hypertensionresponded to hypertonic saline and mannitol therapy.
Seventy-two hours after admission, she underwent liver transplantation. Histology of the explant showed massive A 24-year-old man presented following a polypharmacy liver cell loss consistent with drug-induced injury. Post- overdose including acetaminophen [100 tablets (50 g)], operatively, there was continuing improvement in respira- aspirin, ibuprofen, ketamine and iron tablets 24 h prior tory function but she developed progressive cholestatic to admission. His acetaminophen and iron plasma levels graft dysfunction [bilirubin (Bil) 217 lmol/l] with no were 267 mmol/l and 36.2 mmol/l (202 lg/dl) respec- clear cause found either on the remainder of her blood tively. He was managed as per our standards of care for tests or on imaging studies. Cytomegalovirus (CMV) titre ALF [6] and was commenced on desferrioxamine. He was was not elevated and there was no evidence of rejection transplanted on day 9 following his admission. Histology on liver biopsy.
of the explant showed centrilobular and mid-zonal hepa- Over the course of the next 3 weeks, she remained tocyte loss with marked hepatocellular anisocytosis in the severely jaundiced (Bil 466 lmol/l) and a repeat CT dem- periportal regions, patchy hepatocellular steatosis, ductu- onstrated a patent hepatic artery with new areas of graft lar reaction, and cholestasis.
ischaemia. She underwent a laparotomy to refashion a His initial postoperative course was uncomplicated but perforated bile duct. A repeat liver biopsy did not dem- there were concerns regarding low grade graft rejection onstrate evidence of acute cellular rejection.
for which he received empirical pulse steroid therapy on The postoperative course was complicated by recurrent day 8 post-transplantation. On the following day, he dete- sepsis and development of new cavitating lung lesions riorated clinically with new onset neurological signs. A compatible with a diagnosis of invasive aspergillosis, whole-body CT scan was consistent with features of dis- which was treated with liposomal amphotericin Fig. 1.
seminated septic emboli. Given concerns of invasive fun- The following 6-week period was characterized by an gal infection, he was started on liposomal Amphotericin undulating disease course, with persistent graft dysfunc- and later Voriconazole. A transesophageal echocardio- tion, renal failure and episodes of septic shock. By the gram revealed a suspicious mobile lesion in the right ven- end of this time period, her clinical condition worsened tricular outflow tract Fig. 3.
with new onset neurological signs: CT brain showed He unfortunately continued to deteriorate and, pro- bleeding into an abscess cavity, which was evacuated gressed to brain stem death on day 13 post-liver trans- Fig. 2. Voriconazole was added as culture confirmed inva- plantation. Post-mortem examination was consistent with sive aspergillosis.
disseminated aspergillus infection.
Figure 2 Abscess cavity with bleeding in the left cerebral hemi- Figure 1 CT scan demonstrating cavitating lung lesions.
ª 2011 The Authors Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) e85–e88

Audimoolam et al.
Iron and acetaminophen combination mitochondria; this leads to anaerobic metabolism andthus metabolic acidosis [7]. Myocardial failure, caused by ROS-induced myocardial damage results in profoundshock observed in the later stages of illness [8]. Once hep-atotoxicity has developed the mortality rate can be 50% or more [9]. Liver transplantation as rescue therapy has been reported but primarily in the paediatric setting[9,10].
A clinically useful classification of the effects of iron poisoning into four progressive stages has been proposed: Stage-I (Stage of gastrointestinal toxicity): Stage-II (Stageof apparent stabilization or quiescent phase): Stage-III(Stage of mitochondrial toxicity): Stage-IV (Stage of gas-tric scarring) [11].
Figure 3 Mobile mass (M) in the right ventricular outflow (RVOF) Although all three of our reported cases were caused by tract on echocardiogram. LA, Left atrium; RA, Right atrium; A, Aortic polypharmacy overdose including acetaminophen in two, valve. Modified RV inflow/outflow view.
we feel that concomitant iron ingestion played an impor-tant role in the pathogenesis and eventually resulted inthe fatal outcome of these patients. The rapid progression to ALF is hypothesis generating in terms of a double-hit A 20-year old man was transferred 48 h after polyphar- mechanism. Acetaminophen or drug-induced centrilobu- macy overdose including a significant amount of iron, lar necrosis in combination with a more periportal distri- acetaminophen, amoxicillin, erythromycin, loperamide bution of necrosis caused by iron could have led to rapid and tricyclic antidepressants. The total quantity of the and irreversible liver damage, leaving no room for hepatic drugs ingested was not entirely clear from the presenting regeneration [12]. Hepatic iron concentration was not history. Initial blood tests were consistent with acute analysed in this series although Pestaner et al. has severe liver injury [AST 11555 IU/L, PT 154 s, lactate described excess hepatic iron concentrations (range 1600– 18 mmol/l, ammonia 156 lmol/l]. Admission and pre- 4182 lg/g of dry tissue) from autopsy specimens [13].
transplant listing iron levels were 128 mmol/l (715 lg/dl) Previous case reports of iron overdose, suggest a dose- and 23.7 mmol/l respectively. He was managed as per our related hepatotoxic effect with a serum toxicity threshold fulminant care pathway and was commenced on desferri- of 1700 lg/dl [7]. However, this is not universally oxamine. He was initially listed for a liver transplant but accepted as there is a possibility of idiosyncratic reaction later temporarily suspended from the transplant list 72 h to iron [14] in those with lower serum levels. As all post admission as there was improvement in both his patients in our series had overdosed with suicidal intent, metabolic and neurological state (lactate 1 mmol/l, it was impossible to get an accurate timing of drug (iron) ammonia 100 lmol/l).
overdose; hence serum iron levels may have been mislead- Over the next 10 days, there was evidence of progres- ing. Regardless, all patients were commenced on chelation sively worsening cholestasis (Bil 341 lmol/l) and rising therapy at the referring hospital.
ammonia levels without evidence of raised intracranial The risks of microbial and opportunistic infections are hypertension. This was thought to be driven by sepsis substantial in the setting of ALF [15]. Two patients suc- although cultures remained negative. At that stage, trans- cumbed to opportunistic infections in the form of dis- plantation was not thought to offer a survival benefit over seminated aspergillosis. A higher incidence of invasive medical therapy.
fungal sepsis in patients with evidence of hepatic iron Over the following week, he developed pupillary abnor- overload in the explanted liver has been reported [15,16].
malities; CT demonstrated evidence of cerebral oedema Excess iron in these patients may have been contributory with cerebellar and transtentorial herniation. Post-mor- in the pathogenesis via two possible mechanisms: the tem examination of the liver demonstrated sub-massive enhanced virulence of the micro-organisms in the pres- liver necrosis secondary to drug toxicity.
ence of iron and the impact of iron on host immuneresponses.
All three patients in our series fulfilled King's College Hospital poor prognostic criteria for acetaminophen- Acute iron overdose frequently leads to gastrointestinal induced liver failure [17,18]. Approximately 80 patients disturbances. Intracellular iron exerts its toxic effect on with ALF are currently admitted to our institution ª 2011 The AuthorsTransplant International ª 2011 European Society for Organ Transplantation 24 (2011) e85–e88 Iron and acetaminophen combination Audimoolam et al.
annually, a third of whom will require urgent listing for unit dose packaging requirements; final rule. Fed Regist liver transplantation. The overall 1 year survival of acet- 1997; 62: 2217.
aminophen- or drug-induced ALF in the context of liver 4. Baranwal AK, Singhi SC. Acute iron poisoning: manage- transplantation is 80% [19]. Many patients present in ment guidelines. Indian Pediatr 2003; 40: 534.
MOF with injury severity not dissimilar to the cases pre- 5. Tenenbein M, Kowalski S, Sienko A, et al. Pulmonary toxic effects of continuous desferrioxamine administration The uniformly negative outcome of this admittedly in acute iron poisoning. Lancet 1992; 339(8795): 699.
small series of patients raises the question whether the 6. Auzinger G, Wendon J. Intensive care management of co-ingestion of iron may have influenced the outcome acute liver failure. Curr Opin Crit Care 2008; 14: 2.
7. Robotham JL, Lietman PS. Acute iron poisoning: a review.
negatively. All three patients ultimately succumbed to Am J Dis Child 1980; 134: 875.
infectious complications, in two because of proven 8. Link G, Saada A, Pinson A, et al. Mitochondrial respira- opportunistic pathogens and in the third case because of tory enzymes are a major target of iron toxicity in rat cerebral oedema triggered by sepsis. In the nontransplant- heart cells. J Lab Clin Med 1998; 131: 466.
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the above explained mechanisms could have contributed Toxicol Clin Toxicol 2001; 39: 721.
to the outcome.
10. Kozaki K, Egawa H, Garcia-Kennedy R, et al. Hepatic fail- ure due to massive iron ingestion successfully treated with liver transplantation. Clin Transplant 1995; 9: 85.
11. Covey TJ. Ferrous sulphate poisoning. A review, case sum- We postulate that iron overdose in association with ALF maries, and therapeutic regimen. J Pediatr 1964; 64: 218.
carries a very poor prognosis. Where it is difficult to 12. Witzleben CL. An electron microscopic study of ferrous establish a clear link between iron co-ingestion and poor sulphate induced liver damage. Am J Pathol 1966; 49: outcome, commonly applied risk models for ALF may lack diagnostic accuracy in this setting.
13. Pestaner JP, Ishak KG, Mullick FG, Centeno JA. Ferrous sulfate toxicity: a review of autopsy findings. Biol TraceElement Res 1999; 69: 191.
14. Sumanth R, Daram Hayashi PH. Acute liver failure due to VKA: Collected, analysed and wrote the article. JW, WB, iron overdose in an adult. South Med J 2005; 98: 241.
NH, JO: Reviewed the article. GA: Designed the study; 15. Singh Nina, Sun Hsin-Yun. Iron overload and unique sus- wrote and reviewed the article.
ceptibility of liver transplant recipients to disseminateddisease due to opportunistic pathogens. Liver Transpl2008; 24: 1248.
16. Alexander J, Limaye AP, Ko CW, et al. Association of hepatic iron overload with invasive fungal infection in liver transplant recipients. Liver Transpl 2006; 12: 1799.
17. O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993; 342: 273.
18. Bernal W, Donaldson N, Wyncoll D, et al. Blood lactate as 1. Tenenbein M. Unit-dose packaging of iron supplements an early indicator of outcome in paracetamol-induced and reduction of iron poisoning in young children. Arch acute liver failure. Lancet 2002; 359: 558.
Pediatr Adolesc Med 2005; 159(6): 557.
19. O'Grady JG, Alexander GJ, Thick M, et al. Outcome of 2. Litovitz T, Manoguerra A. Comparison of pediatric poi- orthotopic liver transplantation in the aetiological and soning hazards. Pediatrics 1992; 89: 999.
clinical variants of acute liver failure. Q J Med 1988; 68: 3. Department of Health and Human Services. Iron-contain- ing supplements and drugs: label warning statements and ª 2011 The Authors Transplant International ª 2011 European Society for Organ Transplantation 24 (2011) e85–e88



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