Ming-Yuan Zhang,Jun-Qi Niu,Xiao-Yu Wen,Qing-Long Jin

Abstract

Key words:Benzbromarone;Hepatotoxicity;Liver failure;Liver transplantation;Case report

INTRODUCTION

Benzbromarone is a uricosuric agent that reduces proximal tubular reabsorption of uric acid.Due to reports of severe hepatotoxicity,the use of benzbromarone has been pro-hibited in European and American countries[1];however,the use of benzbromarone is still allowed and frequently occurs in Asian countries[2].In general,reports regarding its potentially severe hepatoxicity are rare.Here,we report a case of liver failure associated with the use of benzbromarone followed by a comprehensive literature review.The search strategy involved searching for the keywords“benzbromarone”,“l(fā)iver injury”,and “l(fā)iver failure” in various data-bases;33 results were retrieved from PubMed and Web of Science (the dates were from the launch of the databases to December 30,2018).A-dditionally,we used the terms “benzbromarone”,“l(fā)iver failure”,and “l(fā)iver injury” in Chinese to search the China National Knowledge Infrastructure website,and three research studies (published between the launch of the database and December 30th,2018) were retrieved.Further selection was performed by searching for reports that directly described the hepatotoxicity of benzbromarone,with eight studies selected (five in English,two in Chinese,and one in Japanese).In our literature review,we describe patient clinical features related to benzbromarone hepatotoxicity,combined with a benefit-risk assessment of benzbromarone.The results will provide additional evidence for evaluating the risk of selecting benzbromarone as a uricosuric drug and for monitoring hepatotoxicity during treatment in clinical practice.

CASE PRESENTATION

Chief complaints

A 39-year-old man was admitted to the hospital for icterus and nausea on July 3,2018.

History of present illness

Seven days before,he suffered from headache and vomiting and was deeply jaundiced.

History of past illness

Four months before admission,he started treatment with benzbromarone (100 mg/d)due to hyperuricemia,but he stopped taking the drug because of the recent jaundice.He had no history of liver disease or other diseases.

Personal and family history

The patient has a history of drinking beer for 10 years and consumes approximately 28 g of alcohol per day.There was no family medical history of note.

Physical examination upon admission

Severe jaundice was found on the skin and sclera,and no signs of encephalopathy were found.The patient's temperature was 36.8 °C,heart rate was 90 bpm,respiratory rate was 18 breaths per minute,blood pressure was 112/77 mmHg,and oxygen saturation was 98%.His body mass index was 23.7 kg/m2.

Laboratory examinations

Laboratory indicators were as follows:Aspartate aminotransferase (AST),170.6 U/L;alanine transaminase (ALT),208.2 U/L;γ-glutamyltransferase (GGT),76 U/L;alkaline phosphatase (ALP),94.2 U/L;total bilirubin,702.5 μmol/L;direct bilirubin,362.5 μmol/L;albumin,34.2 g/L;prothrombin time,33.5 s;prothrombin time activity,25%.Tests for viral hepatitis and human immunodeficiency virus were negative,and autoimmune antibody tests were negative.His blood ammonia level was 145 μmol/L(normal value:9-47 μmol/L).Other laboratory data are provided in Table 1.

Imaging examinations

A computed tomography (CT) scan showed the following:The surface of the liver was irregular,the proportion of each part of the liver was not coordinated,the hilum and hepatic fissure were not wide,and the density of the liver parenchyma was slightly reduced;the intrahepatic bile duct was not dilated.Based on these findings,the patient was suspected of having liver cirrhosis (Figure 1).

Further diagnostic work-up

The patient deteriorated quickly and developed grade II encephalopathy within a few days.We applied the RECUM criteria[3]to evaluate the possibility of drug-induced liver injury (DILI).The RECUM score of this patient was 9,which strongly indicated DILI,and the R value was 5.78,which indicated that this was a case of hepatocellulartype DILI.

MULTIDISCIPLINARY EXPERT CONSULTATION

Ning Ma,MD,Department of Rheumatology,First Hospital of Jilin University

Although there are reports about the hepatotoxicity of benzbromarone,severe liver failure due to this drug is rare,and the liver disease should be treated first.Treatment for gout should not be started under this condition.

Xiao-Dong Sun,MD,PhD,Associate Professor of Department of Hepatobiliary Surgery,First Hospital of Jilin University

The patient is young,and his condition became worse in a relatively short time.

If there is no sign of improvement,liver transplantation should be considered.

Qing-Long Jin,MD,PhD,Professor of Department of Hepatology,First Hospital of Jilin University

The patient should be registered for liver transplantation.Prior to the surgery,continuous plasma exchange (PE) with an artificial extracorporeal liver support system could be performed,and the best supporting treatment should be provided.

FINAL DIAGNOSIS

The final diagnosis of the presented case was acute liver failure due to benzbromarone.

TREATMENT

In addition to albumin and plasma infusion,adenosylmethionine and ornithine aspartate were administered to protect liver function.Additionally,ursodeoxycholic acid was provided orally,and continuous PE was performed six times.However,there was no improvement in the patient's laboratory indices or clinical symptoms(Figure 2).The patient agreed to register for liver transplantation,and he underwent liver surgery 26 d after admission.Liver specimen pathology revealed massive necrosis of liver tissue,cholestasis,and biliary duct hyperplasia (Figure 3).When consulting with the pathology experts,they inferred that the change in the liver on the CT scan might be due to massive necrosis of liver tissue,which caused the shape of the liver to become irregular and atrophic.Liver cirrhosis was not diagnosed in this patient.

Table1 Laboratory data on admission

OUTCOME AND FOLLOW-UP

After liver transplantation,the patient recovered quickly,and jaundice and other symptoms,such as vomiting and headache,disappeared.Laboratory indicators were as follows:AST,26.3 U/L;ALT,72.2 U/L;GGT,165.4 U/L;ALP,77.2 U/L;total bilirubin,25.9 μmol/L;direct bilirubin,13.1 μmol/L;albumin,31.8 g/L;prothrombin time,12.4 s;prothrombin time activity,85%.These indicators were markedly improved compared to the pre-transplantation levels.CT scanning showed a normal change after liver transplantation.The patient left the hospital 95 d after admission,on October 3,2018,and remained well after 6 mo following transplantation.

DISCUSSION

Prevalence of gout and drug treatment

Figure1 Contrast-enhanced computed tomography image.

The prevalence of gout in the general population is 1%-4%,and the annual incidence is 2.68 per 1000 persons.The worldwide incidence of gout has gradually increased due to poor dietary habits,such as the consumption of fast food,lack of exercise,and increased incidence of obesity and metabolic syndrome[4].Gout has an important effect on musculoskeletal function and health-related quality of life.Poorly controlled gout leads to absence from work,health care use,and reduced social participation[5].Previous clinical and pathophysiological data have shown that lowering uricemia to under the saturation point is the best and most reliable way to control gout symptoms in the long term.The most commonly used urate-lowering drugs are allopurinol,febuxostat,uricosurics,and urate oxidases.Benzbromarone is a powerful uricosuric drug;however,after reports of several serious hepatotoxicities,benzbromarone was withdrawn by Sanofi in 2003.Nonetheless,it was still recommended in clinical guidelines for patients with mild/moderate renal impairment[5,6].Currently,benzbromarone is mainly used in Japan,China,Singapore,and other Asian countries.In China,benzbromarone is mainly used for the treatment of gout and hyperuricemia in clinical practice[7].Thus far,most published hepatotoxicity cases due to benzbromarone have been reported in Asian countries (Figure 4).

Hepatotoxicity mechanism of benzbromarone

The hepatotoxicity associated with benzbromarone might be explained by mitochondrial toxicity and subsequent induction of apoptosis and necrosis.Priska found that benzbromarone decreased the mitochondrial membrane potential of isolated rat hepatocytes by 81%.In mitochondria,benzbromarone decreased the state 3 oxidation and respiratory control ratios of L-glutamate,decreased mitochondrial βoxidation,and increased reactive oxygen species production[8].Another study demonstrated that benzbromarone is associated with profound changes in mitochondrial structure,which may be associated with apoptosis[9].Additionally,Wanget al[10]reported that metabolic epoxidation is a key step in the development of benzbromarone-induced hepatotoxicity.

Hepatotoxicity is often associated with cytochrome P450-mediated bioactivation.Early metabolic studies revealed two major hydroxylated metabolites of benzbromarone,1'-hydroxy benzbromarone and 6-hydroxy benzbromarone,in urine,bile,and plasma[11].Further oxidation of 6-hydroxy benzbromarone in human liver microsomes results in the formation of 5,6-dihydroxy metabolites[12].These metabolites of benzbromarone have been reported to induce a transition in mitochondrial membrane permeability,and the metabolites and their reactive intermediates have been associated with liver injury[13-15].According to Kaoru's research,CYP3A4 and CYP2C9 catalyze the formation of 1'-hydroxy benzbromarone and 6-hydroxy benzbromarone,respectively,with CYP2C9 and CYP1A2 further catalyzing the formation of 5,6-dihydroxy benzbromarone in human liver microsomes.The activity of these CYP isozymes might be related to benzbromaroneinduced liver toxicity[16].

Reports of benzbromarone-related hepatotoxicity in the literature

Figure2 Clinical course.

We retrieved eight reported cases of benzbromarone-related hepatotoxicity,for a total of nine including the present case (Table 2):One from the Netherlands,one from Turkey,three from China,and the remaining four from Japan.In addition,the Periodic Safety Update Report listed 11 patients who developed hepatotoxicity from benzbromarone,among whom nine died;however,details of these unpublished data could not be obtained[17].According to the National Center for Adverse Drug Reaction(ADR) monitoring website,533 side effects related to benzbromarone were reported in China before January 10,2015,including 28 cases of liver injury (5.25%),16 cases of mild liver injury (ALT abnormality,1 × ULN ＜ total bilirubin ≤ 5 × ULN,and no or mild symptoms),three cases of severe liver injury (ALT ≥ 10 × ULN,5 × ULN ＜ total bilirubin ≤ 10 × ULN,with severe symptoms and typical signs in physical examination),and nine cases that could not be clearly classified.No liver failure cases were reported on this website,and no more information was provided regarding these patients[7].To date,the case presented here is the first report of liver failure related to benzbromarone in China.

Treatment in our case was successful.Based on suggestions from multidisciplinary consultation,the patient accepted the best supportive treatment,PE as bridge treatment,and liver transplantation,and the follow-up results were good.Our initial diagnosis was confirmed by pathological results of liver tissue sections.The limitation of this research was that we did not assess the activity of CYP isozymes,which might be related to benzbromarone-induced liver toxicity,as these tests were not available in our hospital.

Among all reported cases,four patients have died,three patients recovered after PE,hemodiafiltration,prednisolone,or liver transplantation,alone or in combination,and two patients took benzbromarone for less than 1 mo and recovered after conservative treatment or methylprednisolone therapy.Although benzbromarone hepatotoxicity varied in severity,a high proportion of patients developed acute liver failure,leading to death or emergency liver transplantation.Therefore,medical professionals should exert caution before prescribing this drug,and the risk of hepatotoxicity should be carefully assessed individually,as seven among nine reported patients used other drugs or alcohol when taking benzbromarone,which may aggravate damage to the liver.

Benefits and risks of benzbromarone treatment for gout

Although benzbromarone has been withdrawn in Europe due to serious hepatotoxicity,there is still a debate regarding whether this is in the best interests of gout patients.In 2008,Leeet al[25]presented a benefit-risk assessment of benzbromarone.These authors examined the clinical benefits associated with benzbromarone treatment and compared these benefits with alternative therapies,such as allopurinol and probenecid;they also examined the degree to which the reported cases of hepatotoxicity can be attributed to treatment with benzbromarone and calculated the incidence of benzbromarone hepatotoxicity in Europe(approximately 1/17000 patients).Based on this benefit-risk assessment,the authors recommended the use of benzbromarone for gout and suggested that the risks of hepatotoxicity could be ameliorated by employing a graded dosage increase and regular monitoring of liver function.CYP2C9 status determination and the consideration of potential impacts of inhibition of this enzyme should also be considered[25].

In 2015,the China Food and Drug Administration (CFDA) also performed a benefit-risk assessment of benzbromarone and suggested that the drug has greater benefits than risks in the treatment of gout or hyperuricemia.To prevent hepatotoxicity,the CFDA recommends the following:(1) Benzbromarone treatment should start at a low dose,and during treatment,liver function should be tested regularly;combination with other hepatotoxicity drugs should be avoided;(2)Attention should be paid to the signs of liver injury,such as loss of appetite,nausea,vomiting,diarrhea,and jaundice;once these signs occur,medical advice should be provided in a timely manner;and (3) Arug manufacturers should strengthen ADR monitoring to ensure that product safety information is provided to the public,especially to doctors and patients[7].

Figure3 Liver biopsy specimen staining.

CONCLUSION

In summary,benzbromarone may have benefits in the treatment of gout or hyperuricemia,which support its application.Although cases of severe hepatotoxicity are rare,they can be fatal.Here,we present a successful treatment approach for liver failure associated with benzbromarone.The experience was that the risk of hepatotoxicity should be carefully assessed individually and that hepatotoxicity of benzbromarone should be properly monitored during treatment.

Table2 Characteristics of benzbromarone-induced hepatotoxicity cases

Figure4 Timeline of benzbromarone production and countries with published results regarding benzbromarone hepatoxicity

ACKNOWLEDGEMENTS

We sincerely thank professor Mei-Shan Jin from the Department of Pathology,First Hospital of Jilin University,for kindly helping us with accurate differential diagnosis based on the liver biopsy pathology.