576 Gut 1998;42:576–580 Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases

D Rowbotham, J Wendon, R Williams

Abstract lations as a presenting feature of the illness.3–19 Background—Acute liver failure (ALF) Among these, haematological malignancies are secondary to malignant infiltration of the the most common underlying aetiology, in- liver is rare and is diagnosed often only cluding Hodgkin’s disease,3–5 non-Hodgkin’s after death. lymphoma,6–10 malignant histiocytosis,11–13 and Aims—To determine diagnostic factors the leukaemias (acute and chronic).14–16 Other and particular clinical patterns of illness. infiltrative metastatic malignancies that rarely Methods—Review of case notes from all can cause ALF include adenocarcinomas, patients with ALF secondary to hepatic melanoma, and anaplastic tumours from vari- infiltration admitted to this unit over an 18 ous primary sites.17–23 Making a diagnosis of year period (1978–1995). hepatic infiltration in patients presenting with Results—From a total of 4020 admissions, ALF in such cases is diYcult and requires a 18 patients were identified with ALF high degree of suspicion if evidence of the attributable to hepatic infiltration. Mean underlying primary disease is absent, as is usu- age was 40.7 years. Aetiology was non- ally the case. The finding of lymphadenopathy Hodgkin’s lymphoma in nine patients, along with jaundice points to hepatic lympho- Hodgkin’s disease in three, infiltrative matous infiltration,24 but more commonly the metastatic carcinoma in four, and haemo- presenting symptoms and signs are indistin- phagocytosis with no precipitant cause in guishable from primary hepatic causes and the two cases. Prodromal symptoms were diagnosis often is not made until postmortem. non-specific, but occurred at least two to Death usually is as a direct consequence of the four weeks before onset of ALF, making ALF, rather than due to the underlying malig- the presence of such symptoms of value in nancy. However, early diagnosis and specific diVerential diagnosis of the cause of ALF. treatment of such cases, particularly with the Clinical examination and investigations infiltrating haematological malignancies, can were unhelpful in distinguishing these lead to resolution of the hepatic failure in cases from more usual causes of ALF. response to the destruction of the infiltrating 10 15 Usually, the clinical course was of rapid cell population. deterioration and death from multiorgan Prompted by two recent cases of ALF failure, and only one patient survived. secondary to infiltrative hepatic disease, we Diagnosis was made during life in 15 have reviewed our experience with this rare patients. Histology showed evidence of clinical situation in adults in a single centre widespread hepatocellular necrosis, with over the past 18 years to determine diagnostic diVuse infiltration by tumour cells rather factors and particular clinical patterns of than focal cellular aggregation. illness. Conclusions—Only with accurate histo- logical diagnosis from liver biopsy and Methods and results institution of specific therapy early in the Over the period 1978–1995, 18 patients with management of such patients will the best ALF shown to be attributable directly to chance of recovery be achieved. In every hepatic infiltration (either during life or at case of ALF with prodromal symptoms or autopsy) were transferred to the Liver Failure abnormal imaging, hepatic histology Unit at King’s College Hospital. ALF was should be obtained by liver biopsy as soon defined as the syndrome of hepatic encepha- as possible to diagnose infiltrative hepatic Institute for Liver lopathy and other manifestations of liver cell Studies, King’s College disease. failure in the absence of pre-existing liver (Gut 1998;42:576–580) Hospital, disease and fulfilling criteria as defined by London SE5 9RS, UK 25 D Rowbotham Keywords: acute liver failure; hepatic infiltration; O’Grady et al. J Wendon diagnosis; histology; prognosis The 18 patients comprised 0.44% of the 4020 patients admitted to the Liver Failure Institute of Unit over this time period. Sex distribution of Hepatology, University The liver is the most common site for the 18 cases was equal and age range was College London metastatic tumour deposits with evidence of 16–73 years (mean 40.7 years; median 38 Medical School, hepatic metastases in 36% of all patients who years). The underlying aetiology was non- London, UK 1 R Williams die from cancer. Despite this, derangement of Hodgkin’s lymphoma (NHL) in nine patients, hepatocellular function is unusual until the ter- Hodgkin’s disease (HD) in three, metastatic Correspondence to: minal deterioration,2 although there have been carcinoma (CA) in four, and haemophagocytic Dr D Rowbotham. a number of case reports describing the occur- syndrome with no clear precipitant cause in Accepted for publication rence of acute liver failure (ALF) secondary to two. One patient presented initially with hae- 31 October 1997 infiltration of the liver by malignant cell popu- mophagocytic syndrome, but was diagnosed Acute liver failure secondary to hepatic infiltration 577

subsequently at postmortem to have NHL. have intra-abdominal lymphadenopathy on Mean time from appearance of jaundice to computed tomography (CT) imaging. The admission to this unit was four days (range depth of jaundice on presentation was variable, 2–14). The majority of patients fulfilled the cri- but all patients were icteric. Hepatomegaly was teria for hyperacute liver failure (development more pronounced than in other causes of ALF, of encephalopathy within seven days of onset of with the liver palpable 2–5 fingerbreadths jaundice), with a minority coming within the below the costal margin and with a firm edge. It category of acute liver failure (jaundice to was present with equivalent frequency in encephalopathy time of 8–28 days).25 patients from all diagnostic subgroups. Median time to transfer after admission was Splenomegaly, by contrast, was noted only in six days and median time to diagnosis was eight the NHL and HD subgroups. Postmortem days after admission to hospital. Diagnosis of examination of the enlarged spleens revealed the underlying disease process was established infiltration by tumour cells as the cause of the by the referral hospital in only four patients. splenomegaly in all cases. One half of patients Overall diagnosis during life was achieved in 15 were febrile at presentation despite only one patients on the basis of histological analysis of third reporting fever as a presenting symptom. tissue from liver biopsy (seven patients), bone Diagnosis in the three patients who pre- marrow biopsy (five), lymph node biopsy sented with haemophagocytic syndrome was (two), and by appearances seen at ultrasound based on histological analysis of bone marrow scanning (one). In the remaining three pa- aspirate and trephine biopsy. One patient was tients, a postmortem diagnosis was made from discovered subsequently to have NHL, but in histological analysis of hepatic tissue in two the remaining two no precipitant cause could patients and lymph node tissue in one. In all, be established despite extensive antemortem 19 biopsies were performed in 16 patients and and postmortem investigation. Both of these before a diagnosis could be made, three patients were young women aged 30–40 years. patients underwent biopsy of more than one One of these patients gave a history of three tissue (two bone marrow/liver combinations weeks of cough and sore throat for which she and one bone marrow/lymph node). Bone had been given a seven day course of oral marrow samples were obtained from nine amoxycillin, but all bacteriological and viral patients, lymph node tissue from two, and markers were negative. The other patient had hepatic tissue from eight. Liver biopsies were no preceding symptoms and was negative for performed using a percutaneous needle ap- the whole range of viral and bacteriological proach in five patients, the transjugular route in investigations. Neither patient had taken any one, and at laparotomy in two. other drugs, either prescribed or self medi- There was a history of previous therapy for cated, nor were they pregnant. the same disease in 1/8 NHL patients and in As most patients were transferred early on in 2/3 HD cases. Two patients who developed the course of ALF, notable coagulopathy was ALF secondary to NHL were receiving immu- not a feature on admission (INR range 1.0–6.1, nosuppressive therapy at the time of presenta- median 3.02), but progressed rapidly following tion with ALF. One of these was on a combina- admission (median maximum value of INR tion of prednisolone, azathioprine, and 6.1). Thrombocytopenia was a feature in all cyclosporin A as routine immunosuppression patients (platelet count range 10–326 × 109/l, following cardiac transplantation two years median 60), with the majority also displaying a earlier. This patient showed a significant IgM mild anaemia (haemoglobin range 6.3–13.6 titre to Epstein-Barr virus, but was known to g/dl, median 10.5) and an increased peripheral have suVered very recently from infectious blood leucocyte count (range 0.9–26.0 × 109/l, mononucleosis. Another patient with ALF sec- median 7.4). None of these results were of ondary to NHL was taking a combination of value in discriminating these patients from prednisolone and azathioprine as treatment for those with ALF from other causes. Electrolyte an autoimmune haemolytic anaemia diagnosed disturbances were common, especially hy- two years previously. ponatraemia (sodium range 117–146 mmol/l, Prodromal symptoms were present usually median 129; potassium range 2.9–6.8 mmol/l, for at least two to four weeks before develop- median 4.1) along with evidence of renal ment of ALF, although the range was wide: five impairment (urea range 4.1–50 mmol/l, me- days to two months (mean 28 days). No patient dian 20.1; creatinine range 51–645 µmol/l, developed ALF without prodromal symptoms. median 119). Liver function tests showed The usual prodromal symptoms were non- impairment of synthetic function with low specific, comprising malaise (in 50% of cases), serum albumin (range 18–39 g/l, median 29) in weight loss (39%), right upper quadrant addition to evidence of severe hepatocellular abdominal pain (39%), and fever (33%). Jaun- injury with high serum aminotransferase levels dice appeared later in the disease course and (aspartate aminotransferase range 79–2180 heralded the onset of ALF. Mean time from IU/l, median 358; ã glutamyl transpeptidase appearance of jaundice to hospital admission range 78–768 IU/l, median 218), although was four days (range 2–14 days). serum aminotransferase were not as high as has Physical signs on admission were of help in been found in other causes of ALF. The level of diagnosis only in respect to the NHL sub- jaundice on admission was variable in the group, in whom palpable lymphadenopathy majority of patients (bilirubin median 187 was present in 5/9 cases. No other patient had µmol/l), although a minority were deeply jaun- clinical lymphadenopathy, although two pa- diced (bilirubin >100 µmol/l in 14 patients and tients (one HD and one CA) were found to >350 µmol/l in three). Three patients with 578 Rowbotham, Wendon,Williams

infiltrative lymphoma showed predominantly intravenous chemotherapy (cyclophospha- cholestatic jaundice with gross elevation of mide, vincristine, doxorubicin, and oral ster- alkaline phosphatase values (>1500 IU/l), but oids) four weeks later. He subsequently made a most patients showed only modest elevation full recovery. (range 121–4620 IU/l, median 522). Histological diagnosis was made from the Radiological imaging, by ultrasound scan- specific features of the infiltrating cell popula- ning in 16 and CT in seven patients, although tion. Whether on needle biopsy, or at postmor- not providing a definitive diagnosis, was of tem, the infiltrating cell populations were value in revealing the presence of intra- spread diVusely throughout liver tissue with no abdominal lymphadenopathy or confirming evidence of localised or focal cellular aggrega- hepatosplenomegaly in eight patients. In- tion. There was no association between the creased reflectivity and abnormal echotexture extent or pattern of cellular infiltration and of the hepatic parenchyma, typical of infiltra- underlying aetiology. Large areas of liver tive hepatic disease, was recorded in eight showed evidence of necrosis, such necrotic patients. change ranging from subacute to severe. Inter- estingly, necrosis was not confined to infiltrated Clinical course and outcome areas of hepatic tissue, with non-infiltrated tis- The clinical course following admission, with sue also showing evidence of necrosis. the exception of one patient, was of rapid dete- rioration and death. Overall mortality was Discussion 94%, the only survivor being from the NHL This series, limited to adults only, adds consid- subgroup. Median time to death following erably to the reported experience of ALF admission was six days (range 1–51 days). secondary to hepatic infiltration. The findings Death was caused in all patients by multiorgan confirm previous reports with haematological failure due to combinations of cardiovascular malignancies being implicated in the majority collapse, acute lung injury, and renal failure in of cases. Of these, NHL is consistently the addition to hepatic failure. In the 24 hours commonest cause. Although liver involvement before death, all patients had clinical evidence is found in 16–22% of cases of untreated of sepsis (fever, peripheral blood leucocytosis, NHL,26–28 such hepatic disease is most often urine microscopy, or radiological changes of asymptomatic. It can be associated, on occa- pneumonia). sion, with hepatomegaly and derangement in The progressive clinical deterioration and liver function tests, especially a rise in alkaline high mortality occurred despite the prompt phosphatase,24 26–28 but without liver failure. In administration of specific treatment (chemo- none of the present patients, however, was therapy, corticosteroids, and/or immunoglobu- there evidence of such hepatic involvement lin) to 11 of the 15 patients in whom an ante- antedating presentation with ALF. In cases of mortem diagnosis had been established. Two ALF secondary to lymphoproliferative disease, patients with NHL were considered too unwell a history of previous treatment for the same to receive any form of chemotherapy and two disease was apparent in over one quarter of patients found to have infiltrative metastatic cases. This suggests that recurrence of a previ- carcinoma were treated initially with chemo- ously treated lymphoma may predispose to a therapy on the clinical suspicion of underlying subsequent preferential aggressive invasion of lymphoproliferative disease. The haemophago- the liver, although by what mechanism is cytic syndromes with no precipitant cause unclear. were treated empirically with corticosteroids, One patient, found to have underlying NHL, intravenous acyclovir, and chemotherapy presented with ALF secondary to haemo- (etoposide in one patient, methotrexate in the phagocytosis. Such a condition does not occur other). Their condition improved initially in as a primary event. Potential precipitants of the first few weeks, but in both cases the acute haemophagocytic syndrome include viral haemophagocytic syndrome relapsed leading infection,29–34 bacterial or fungal infection,35–38 to rapid deterioration and death within three metabolic disturbance,39 inflammatory and six weeks of admission respectively. arthropathy,40 and pregnancy41 in addition to The one survivor in the series was a 27 year leukaemias and lymphoproliferative old man with NHL who had presented with a disease.42–44 The possibility of lymphoma as a 17 day history of diarrhoea, vomiting, fever, cause of the acute haemophagocytic syndrome and weight loss and five days of increasing in the two patients without a clear precipitant jaundice. He had palpable hepatosplenomegaly aetiology seems very unlikely, since investiga- and CT imaging revealed retroperitoneal and tion during life and postmortem examination para-aortic lymphadenopathy. Rapid deteriora- failed to provide evidence of such disease. tion occurred with coagulopathy (INR 3.9), a It is important, both in terms of early rising alkaline phosphatase (>1000 IU/l), and diagnosis and prompt initiation of treatment, encephalopathy (grade 3). A percutaneous liver to recognise symptoms associated with the biopsy, performed by the referring hospital four underlying disease from those due to the days after presentation, confirmed a diagnosis development of ALF. Disease related prodro- of infiltrative NHL. He was given intravenous mal symptoms were usually present at least two cyclophosphamide the next day and trans- to four weeks before development of ALF. No ferred to our unit. Combination intravenous patient developed ALF without prodromal chemotherapy (doxorubicin, vincristine, corti- symptoms. This is of diagnostic help in distin- costeroids, and immunoglobulin) was insti- guishing these cases from ALF due to other tuted immediately, with a second course of causes. The depth of jaundice on admission Acute liver failure secondary to hepatic infiltration 579

was lower in this series than with other causes The potential role of cytokines in ALF asso- of ALF19 although this finding was variable and ciated with malignant disease, but especially in unhelpful in distinguishing these cases from lymphomas, has been the cause of much recent ALF due to other causes. interest. It has been suggested that massive Palpable lymphadenopathy, which may have cytokine release from lymphomatous cells may led to suspicion of haematological malignancy, cause interlobular bile duct destruction and was present in surprisingly few cases. The portal fibrosis, the so called vanishing bile duct apparent predilection of the tumours in these syndrome.46–49 Cytokines may damage bile patients to infiltrate the liver, often in isolation, ducts directly or may result in the recruitment in preference to the peripheral lymphatic of other immunological eVector cells, leading system, raises the possibility of a phenotypic ultimately to bile duct destruction. This might lymphomatous subtype with selective organ account for the observed disparity between invasion. In view of the diagnostic implications relatively minor lymphomatous cell loads and in such patients, any uncertainty regarding the the very severe cholestasis that occurs in underlying aetiology in a patient with ALF reported cases of idiopathic Hodgkin’s associ- must be clarified by liver biopsy (or bone mar- ated cholestasis.46 50 Interleukin 2, which is one row biopsy) in order to achieve an accurate of the cytokines released from lymphoma cells, diagnosis. This is of particular importance in for example, has been shown to induce hepato- relation to the possible use of orthotopic liver cyte toxicity by activating KupVer cells with transplantation for ALF. Secondary malignant release of further cytokines (such as tissue infiltration of the liver is an absolute contrain- necrosis factor) leading to activation of circu- dication to orthotopic liver transplantation. lating leucocytes and hepatic sinusoidal en- Mortality in this series is in agreement with dothelial cells. The subsequent leucocyte and previously published reports. The sole survivor platelet adhesion to sinusoidal endothelium from our series had a number of favourable physically impedes the sinusoidal microcircula- factors including his young age and a diagnosis tion resulting in microscopic hepatic of high grade NHL, a tumour likely to exhibit ischaemia.51 Such mechanisms, if occurring a good response to chemotherapeutic interven- diVusely, may lead to widespread hepatocyte tion. Nevertheless, it was the attainment of a dysfunction and ALF. It is possible that definitive histological diagnosis by percutane- massive release of cytokines from malignant ous liver biopsy that allowed prompt adminis- cell populations anatomically distinct from the tration of specific chemotherapy. A histological liver may lead to ALF in a similar way, since diagnosis was obtained from bone marrow or occasional instances of fulminant hepatic lymph node biopsy as often as from liver failure have been described in non-metastatic biopsy, reflecting the preponderance of haema- renal cell carcinoma.52 tological malignancies in this series. Although It has been shown by using genetically the risks of percutaneous biopsy are increased tagged cells that metastatic cell subpopulations in such cases due to concurrent coagulopathy can outgrow their non-metastatic counterparts and/or thrombocytopenia, with appropriate within the primary tumour,53 suggesting that fresh frozen plasma and/or platelet transfusion the metastatic potential of a primary tumour cover, there was no additional morbidity or may increase during the course of its growth. mortality as a result of the biopsies carried out Subsets of cells within a tumour may show a in this series. predilection for certain metastatic sites, but the Within the spectrum of malignant disease, relevance of this to human cancers is the liver is the most common site for metastatic unproven.54 Nevertheless, the possibility of tumour deposits (36%), the incidence being subgroups of cells within a cancer that express highest (48%) for tumours arising within the 1 varying degrees of aggression or malignancy portal venous drainage area. Metastatic spread may be an important factor in determining not to the liver occurs usually as discrete tumour only the site of metastasis, but possibly also the deposits, either single or multiple, or less com- occurrence of ALF in rare cases. Recurrence of monly as hepatic invasion by sheets of a previously treated lymphoma could also be malignant cells in a more diVuse pattern. Vari- explained on this basis. In this series, a history ous mechanisms have been suggested to of previous treatment for the same disease was explain the association of hepatic infiltration present in over one quarter of patients with and ALF including tumour infiltration of the lymphoma. This fact raises the possibility that biliary tree, hepatic vasculature, and hepatic chemotherapy may change or enhance the parenchyma. Invasion of the extrahepatic malignant behaviour of such tumours with biliary system leads to obstructive jaundice recurrent tumour cell subpopulations possess- rather than ALF, but infiltration of small intra- ing enhanced malignant properties which pref- hepatic bile ducts may result in extensive erentially target and invade the liver. cholangitis, duct necrosis, and ALF.45 Obstruc- tion of hepatic venules by tumour may result in hepatocyte ischaemic injury and necrosis,15 or This work was presented in abstract form (Acute liver failure due to hepatic infiltration; D S Rowbotham, J A Wendon, R massive sinusoidal infiltration by malignant Williams) at the Liver Intensive Care Group of Europe, ninth cells is likely to cause sudden ischaemia and meeting in Helsinki, 1996. subsequent hepatocellular necrosis.18 Alterna- tively, rapid replacement of vast areas of 1 Willis RA. The spread of tumours in the human body. London: hepatic parenchyma by malignant cells may Butterworths, 1973. 2 Cello JP, Grendell JH. The liver in systemic conditions. In: lead to a critical mass of hepatocyte destruction Zakim D, Boyer TD, eds. 15 17 19 Hepatology. A textbook of liver dis- and subsequent ALF. ease. Philadelphia: WB Saunders, 1990:1423–5. 580 Rowbotham, Wendon,Williams

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