Hepatic Transplant in Acute Alcoholic Hepatitis: A Case Report

Case Report Mestrado Integrado em Medicina HEPATIC TRANSPLANT IN ACUTE ALCOHOLIC HEPATITIS: A CASE REPORT Ana Raquel Génio Freire Orientador: Dr. Filipe Gaio Nery Porto, 8 de Junho de 2012 Liver transplant in alcoholic hepatitis CASE REPORT Hepatic Transplant in Acute Alcoholic Hepatitis: A Case Report Transplante Hepático na Hepatite Aguda Alcoólica: A propósito de um caso clínico Ana Raquel Génio Freire – ICBAS-UP [email protected] 2 Liver transplant in alcoholic hepatitis Abstract Alcoholic liver disease is a global health issue. This wide-ranging entity encompasses a distinct clinical syndrome induced by alcohol consumption known as acute alcoholic hepatitis. The clinical spectrum ranges from asymptomatic to symptomatic presentation with analytical changes, hepatic failure and death. With a 28day mortality of up to 50%, treatment is essential. Within the various therapeutic agents proposed for treatment of acute alcoholic hepatitis, corticosteroids are still the first option in clinical practice. Nevertheless, it is not effective in all cases. In those patients defined as non-responders, corticotherapy does not improve long term survival, and thus a new approach to treatment is necessary. It is in these cases that we may look to hepatic transplant as a possible treatment route. Hepatic transplant in patients with acute alcoholic hepatitis, however, has proven quite controversial. There is a reluctance to allot the scarce organs available to patients whom the public often views as responsible for their own disease. The concern that patients would relapse post-transplant has contributed to the implementation of a 6 month alcohol abstinence period still required for patients to be considered for transplant in some countries. Conversely, new studies point away from the use of this 6 month rule and instead enforce the implementation of selecting patients for transplant based on other criteria of greater importance to outcome. We report the case of a 56 year old male presenting with acute alcoholic hepatitis, non-responder to therapy with corticosteroids, that was posteriorly proposed for hepatic transplant. Key Words: acute alcoholic hepatitis, hepatic transplant, corticosteroids, nonresponder, alcoholic abstinence. 3 Liver transplant in alcoholic hepatitis Resumo A doença hepática alcoólica é um problema de saúde global. A hepatite aguda alcoólica é caracterizada por ser uma síndrome clínica distinta induzida pelo consumo de álcool. O espectro clínico vai desde um estado assintomático até sintomas associados a alterações analíticas, insuficiência hepática e morte. Com uma mortalidade aos 28 dias de até 50%, um tratamento eficaz é essencial. Dentro dos vários agentes terapêuticos propostos para o tratamento, os corticosteróides constituem ainda a primeira opção na prática clínica. No entanto, a corticoterapia não é eficaz em todos os casos. Nos doentes definidos como não-respondedores, a corticoterapia não aumenta a sobrevida a longo prazo e, assim, uma nova abordagem terapêutica é necessária. Consequentemente, o transplante hepático torna-se nestes casos uma opção atraente. O transplante hepático em doentes com hepatite aguda alcoólica, no entanto, permanece um assunto bastante controverso. Existe uma relutância em disponibilizar órgãos (que são escassos) para transplante a doentes que o público geralmente percepciona como tendo infligido em si a sua doença. A preocupação de que os doentes poderão vir a sofrer de uma recaída após o transplante, contribuiu para a implementação de um período obrigatório de 6 meses de abstinência alcoólica, ainda necessária para que tais doentes sejam considerados para transplante hepático em alguns países. Contudo, vários estudos recentes têm vindo a valorizar a criteriosa selecção de doentes candidatos a transplante hepático em detrimento da regra dos seis meses. Reportamos o caso clínico de um doente de 56 anos de idade que se apresentou com hepatite aguda alcoólica, não-respondedor à corticoterapia, sendo posteriormente 4 Liver transplant in alcoholic hepatitis submetido a transplante hepático. Um resumo mais detalhado pode ser consultado no Apêndice. Palavras-chave: hepatite aguda alcoólica, transplante hepático, corticosteróides, nãorespondedor, abstinência alcoólica. 5 Liver transplant in alcoholic hepatitis Introduction With increasing alcohol consumption worldwide, alcoholic liver disease (ALD) has become a significant global health concern.1 According to the World Health Organization (WHO), alcohol consumption is the third leading cause of premature death and disability in the European Union and can be attributed to up to 9.2% of all disability adjusted life years.2-4 Acute alcoholic hepatitis (AAH) is a distinct clinical syndrome induced by alcohol consumption with a particularly poor prognosis with a 28-day mortality ranging from 30%-50%.5 This syndrome encompasses a clinical spectrum ranging from asymptomatic to symptomatic forms with analytical changes, hepatic failure and death. The actual prevalence of AAH is difficult to gauge because it can be completely asymptomatic and many patients are underdiagnosed, though a prevalence of approximately 20% was observed in a cohort of 1604 patients with alcoholism who underwent a hepatic biopsy.5 In addition, it is estimated that about 35% of alcoholics suffer from AAH, most cases occurring before the age of 60 years.5-6 In general, the risk of liver disease is associated with the pattern of drinking, the type of drink consumed and the amount of alcohol consumed.2,5,7 A daily intake of alcohol for 10-12 years with doses in excess of 40-80 g/day for males and 20-40 g/day for females are generally needed to cause alcoholic liver disease.8 However, current European guidelines refer that even the ingestion of small amounts of alcohol (< 25 g/day) may be enough to induce alcoholic liver disease.9 Ethnicity,2,5,10 as well as other risk factors including obesity5, iron overload, concomitant infection with viral hepatitis and genetic factors are also implied.2 6 Liver transplant in alcoholic hepatitis The diagnosis of ALD is based on a combination of features, including a history of significant alcohol intake, clinical evidence of liver disease, and supporting laboratory abnormalities.2,8 AAH is associated with a broad clinical picture including asthenia, pain in the right hypochondrium, fever, tachycardia and frequently jaundice. Typically, the ratio of aspartate aminotransferase to alanine aminotransferase (ASAT/ALAT) is approximately 2:1.2 Other common laboratory abnormalities include hyperbilirubinemia, leukocytosis and anemia.2,8 In addition to the laboratory characteristics common to all forms of ALD, AAH is typically associated with elevated concentrations of gamma-glutamyl transpeptidase and of alkaline phosphatase.11 In addition to nutritional support and ensuring alcohol abstinence,2,8,12-13 other therapeutic agents such as corticosteroids,14-15 anti-oxidant therapy,12,16-18 pentoxifylline,19-20 TNF-α antibodies, propylthiouracil, colchicine, S-adenosyl-Lmethionine,8,21-23 and even molecular adsorbent recirculating system (MARS)21-22,24-25 have been proposed. Of these therapies, only corticosteroids have found a place in regular practice, although even here, the data on their efficacy are controversial. Pentoxifylline and MARS do, however, show promise in specific cases. In addition, the association of N-acetylcysteine to corticosteroid treatment has recently been found to improve short term survival, and may be considered as an adjunct to standard treatment.18 As a result, standard medical treatment for patients with AAH may include the administration of corticosteroids to those who have a Maddrey discriminant function (DF) greater than or equal to 32, or more recently, a Glasgow Alcoholic Hepatitis Score (GAHS) greater than or equal to 9.2,8,21,26 The Lille score will posteriorly evaluate the response to corticosteroids after 7 days, giving an indication of which patients will respond to and therefore benefit from maintenance of the corticoid therapy.27-28 Patients 7 Liver transplant in alcoholic hepatitis who do not respond to corticotherapy have a poor survival rate.29 Consequently, new strategies are needed in order to address these cases. Chronic liver disease with progression to cirrhosis and its inherent complications are the second most common reason for liver transplantation in the United States and Europe.30-31 It is usual practice in most programs in North America and Europe to require patients with ALD to be abstinent for 6 months prior to transplantation.22,32 However, the United Network for Organ Sharing (UNOS) and the French Consensus Conference do not consider it to be a rule since 2005.29,33 For patients with severe alcoholic hepatitis who do not respond to corticosteroid treatment, deferring transplantation for six months may not be an option due to precocious mortality.22 In the following report the case of a male patient aged 56 years who presented with AAH, non-responder to corticotherapy, with progression to liver failure and posteriorly subjected to hepatic transplant, will be addressed. The role of hepatic transplant in context of alcohol intake will be discussed as well as the ethical implications inherent to the realization of this as of yet nonconsensual procedure. 8 Liver transplant in alcoholic hepatitis Case Report A 56-year-old autonomous male, married with a structured family life, with a history of alcohol ingestion greater than 100 g/day since the age of 30 in the context of social drinking and accompanying meals, presented with edema of the right foot one month prior to hospital admission. At this time the patient was observed by his family physician, and upon investigation, an altered hepatic profile was the only significant finding. The patient claimed to have ceased his alcohol consumption at this point in time. Previous analytical studies dating as far back as 2002, registered elevated liver enzymes, with a predominance of ALAT over ASAT, however, the patient was not alerted to this fact by his family practitioner. Two weeks after the initial foot edema, the patient noted bilateral edema of the legs and a marked increase in abdominal perimeter, without the perception of jaundice by the patient himself or family members. The patient sought medical attention upon onset of these symptoms and was medicated with furosemide and spironolactone. After 4 days of treatment with diuretics with no medical improvement, the patient was admitted to the hospital for further investigation. Upon admission, laboratory findings exhibited a total bilirubin of 12.2 mg/dL (normal range, 0.2-1.2 mg/dL), ASAT of 351 U/L (normal range, 5.0-34.0 U/L), ALAT of 202 U/L (normal range, < 55.0 U/L), a hemoglobin value of 12.5 g/dL (normal range, 13.0-18.0 g/dL), a platelet count of 151000/μL (normal range, 150000-400000/μL), a leucocyte count of 7700/μL (normal range, 4000-11000/μL), a C-reactive protein of 4.12 mg/dL (normal range, < 0.50 mg/dL), and an INR of 3.4. Imaging tests also performed at this time depicted a pattern compatible with cirrhosis. Having excluded a potential spontaneous bacterial peritonitis and pondering the possibility of being in the presence of an acute alcoholic hepatitis, with an elevated 15 Liver transplant in alcoholic hepatitis voluntary acetaminophen poisoning, nor to intravenous-drug users with acute hepatitis B virus infection.28,36 In fact, the European Association for the Study of the Liver (EASL) already consider OLT as a treatment option in highly selected patients in their recent clinical practical guidelines on the management of alcoholic liver disease.9 It is thus vital that the public are made aware that patients are only offered transplantation if they fail to recover after a period of abstinence and medical treatment and that the incidence of significant post-transplant recidivism is low.21 The continuing imbalance between the few available livers and the increasing numbers of patients on waiting lists has led physicians to develop prognostic factors to determine disease severity in order to list and allocate donor organs to the sickest patients.37 Among available scores, the MELD is now considered the gold standard when selecting candidates for liver transplantation.38-39 Optimal timing for liver transplantation in alcoholic patients varies drastically between transplant programs, and decisions on transplant eligibility should be made on an individual basis, with careful prediction of short-term survival.33 An American conference held in 2003 stated that the Model for End-Stage Liver Disease meets the goal of providing a system that emphasizes the urgency of the candidate.33 Candidates with a MELD score < 15 had a lower mortality risk than transplanted patients with a similar MELD score.33 With scores of 18-20, studies show the mortality risk was lower among transplant recipients when compared with candidates.39 Survival benefit increased with increasing MELD score with recommendations stating that the best option is to list patients with a MELD score ≥ 15.37 Some investigators, however, have suggested that a cutoff point at 40 may be used to define a patient as too ill for liver transplantation.33 Nonetheless, although recipients with a MELD score ≥ 40 had greater post-transplant mortality, their survival rate was still greater than that for candidates who were not transplanted.39 According to 16 Liver transplant in alcoholic hepatitis the study conducted by Mathurin et al. (2011), the cumulative 6-month survival rate (±SE) was higher among patients who received early transplantation than among those who did not (77±8% vs. 23±8%).29 Our patient at time of transplant proposal had a MELD score of 39. Even though we have ascertained that regardless of the high MELD score, transplanted patients in those cases continue to have a higher survival rate in comparison to those not transplanted, we can speculate that the negative outcome and consequent death in our patient could have been predicted based on the severity pretransplant as denoted by the MELD score. With exception of those patients considered to be too ill, the outcome for patients who undergo transplantation for ALD is similar to that seen in patients transplanted for other forms of end-stage chronic liver disease.22,30 The study conducted by Tome et al. (2002) clearly demonstrated that survival after liver transplantation in patients with alcoholic cirrhosis plus alcoholic hepatitis detected in explanted liver was similar to that of patients transplanted for non-alcoholic disease.40 In addition, it is known that ALD patients post OLT have reduced incidence of acute cellular rejection.31 Chronic ductopenic rejection is also reportedly less common or the same in the patients receiving OLT for ALD from those for other indications.31 Infections, on the other hand, are reportedly more common following OLT in patients with ALD. The incidence of bacterial infections is greater in these patients while the incidence of cytomegalovirus infection is comparable to those patients transplanted for non-alcoholic liver disease.31 Mathurin et al. (2011) reported that 5 of the 6 deaths post-transplant of a total of 26 case patients, were premature and a consequence of infection, 4 deaths of which were attributed to invasive aspergillosis.29 Even before transplantation, infection appears to be a consequence of absence of improvement in liver function, as assessed by response to therapy.41 In addition, we can 17 Liver transplant in alcoholic hepatitis not rule out the brief course of corticotherapy in non-responders as a contributing factor, at least in part, to susceptibility to infection.41 Studies evaluating the usefulness of fungal prophylaxis as well as prophylactic antibiotics before transplantation, duration of glucocorticoid use before and after transplantation, and the tailoring of immunosuppressive regimens29,41 are needed in order to develop possible strategies for improving outcome in face of infection. Sequential screening for possible infections may also have some value in these patients. Choosing the appropriate moment for transplantation is in fact crucial. Optimal timing in regards to transplantation will be imperative in avoiding the adverse effects of intervening too early or too late. We can speculate that the patient presented in this case report, although considered to be the “perfect candidate”, was not transplanted within the ideal window of time, leading to additional complications post-transplant and consequently death. 18 Liver transplant in alcoholic hepatitis Conclusion The management of patients with alcoholic liver disease is a challenge. The high rate of mortality associated with severe AAH urges the need for more effective treatment options. Whereas corticotherapy may be of worth in those patients defined as responders, it is a different question when we discuss those that are defined as nonresponders. In this group of patients new therapeutic options are necessary. Hepatic transplant can be one of those options in selected patients that fulfill various criteria including the absence of other comorbidities, social integration and the existence of a strong support group. The recent EASL clinical practical guidelines on the management of alcoholic liver disease already consider OLT in highly selected patients, altering the paradigm regarding the conduct and treatment of AAH. Alcoholic hepatitis is indeed an acceptable indication for liver transplant, as survival in well selected patients after transplantation is similar to those seen in patients who receive grafts for other causes. Relapse to heavy drinking is uncommon and as yet, has not shown to adversely affect outcome. At present, there is no evidence to deny liver transplantation to patients with shorter periods of abstinence based on either poorer survival or higher relapse rate. Decisions on transplant eligibility, however, should be made on an individual basis, as patient selection is important for rationing scarce organs. Although more data are required, the benefit of OLT in patients with severe AAH who fail to respond to corticotherapy is a promising area of research. While this is true, early liver transplantation is relevant only for a minority of patients whereas new therapeutic strategies are urgently needed for the majority of non-responders. As well, we need to better define the optimal timing to transplant eligible patients. In addition to 19 Liver transplant in alcoholic hepatitis timing, new measures must also be considered in order to circumvent possible infections post-transplant in these patients. 20 Liver transplant in alcoholic hepatitis References 1. Yu C, Xu C, Ye H, et al (2010) Early mortality of alcoholic hepatitis: A review of data from placebo-controlled clinical trials. World J Gastroenterol 16(19):2435-2439. 2. 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