Acute liver failure (ALF) is a medical emergency with high mortality. Accurate etiological diagnosis, intensive liver support, and liver transplantation are critical for the management of these patients. Malignant infiltration of the liver uncommonly results in ALF. Diffuse infiltration can be missed by imaging, particularly in early stages, and biopsy is often required to clinch the diagnosis. We report a case of ALF due to diffuse liver metastasis.
ACG CASE REPORTS JOURNAL CASE REPORT | LIVER Acute Liver Failure due to Miliary Liver Metastasis Charles A Lavender, MD1, Jessica Stout, MD1, Hui-Yong Chung, MD2, Michael Johnson, MD3, and Ragesh B Thandassery, MD1 Division of Gastroenterology, Department of Medicine, Central Arkansas Veterans Health Care System, Little Rock, AR Diagnostic and Therapeutic Imaging Services, Central Arkansas Veterans Health Care System, Little Rock, AR Division of Pathology, Department of Medicine, Central Arkansas Veterans Health Care System, Little Rock, AR ABSTRACT Acute liver failure (ALF) is a medical emergency with high mortality Accurate etiological diagnosis, intensive liver support, and liver transplantation are critical for the management of these patients Malignant infiltration of the liver uncommonly results in ALF Diffuse infiltration can be missed by imaging, particularly in early stages, and biopsy is often required to clinch the diagnosis We report a case of ALF due to diffuse liver metastasis INTRODUCTION Infiltration of the liver by malignant cells can rarely result in acute liver failure (ALF) In the United States ALF study group analysis, ALF due to malignant infiltration was seen only in 27 (1.4%) of 1910 cases with lymphoma and breast cancer being the most common primary causes.1 Patients usually present with abdominal pain and elevated liver function tests with synthetic dysfunction Diagnostic imaging is often unrevealing, given the typical diffuse nature of malignant spread.1,2 More than half of the cases not show a distinct liver mass on imaging and require liver biopsy for confirmation Most of the time, ALF secondary to malignant infiltration has a very dismal prognosis.1,2 CASE REPORT A 65-year-old man without a medical history of liver disease presented with jaundice, progressive abdominal pain, abdominal distension, and weight loss over a 6-week period He was icteric on examination, but there were no other features of chronic liver disease or hepatomegaly Liver function tests were acutely elevated over week: alanine transaminase 199 IU/L, aspartate transaminase 492 IU/L, alkaline phosphatase 562 IU/L, and bilirubin total 28.5 and direct 10.5 mg/dL (from admission values of 9.4 and 5.65 mg/dL, respectively) from a normal baseline months earlier Acute viral markers, autoimmune markers, acetaminophen level, hemolytic workup, ethanol, and drug screen were negative There was no history of significant alcohol intake in the past A detailed medication review did not reveal any hepatotoxic medications or herbal and dietary supplements There was no hemodynamic instability early in the hospital course or any features of congestive heart failure Ultrasound on admission followed by abdominal computed tomography (CT) scan revealed hepatomegaly, trace ascites without any other features of chronic liver disease, and multiple small peripheral portal vein thrombi (Figures and 2) Over the next few days, he deteriorated rapidly with progressive hepatic synthetic dysfunction, coagulopathy (international normalized ratio 4.9, prothrombin time 45.7 with control 12 seconds; baseline international normalized ratio was and on hospital admission was 3.1), and encephalopathy consistent with ALF with a Model for End-Stage Liver Disease-Sodium of 42 Urgent orthotopic liver transplant (OLT) evaluation was initiated Meanwhile, he decompensated with progression to multiorgan failure requiring ventilatory and double ionotropic support The white blood cell count was uptrending (peaked at 13.4 k), and complete infectious workup was negative Repeat ultrasound for abdominal distention on day showed innumerable hyperechoic nodules throughout the liver A transjugular liver biopsy was obtained, and histopathology demonstrated metastatic small-cell carcinoma of high-grade neuroendocrine differentiation without background cirrhosis (Figure 3) Metastatic liver disease leading to liver failure is ACG Case Rep J 2020;7:e00294 doi:10.14309/crj.0000000000000294 Published online: March 16, 2020 Correspondence: Ragesh B Thandassery, MD, Gastroenterology/Hepatology Staff Physician and Liver Program Director, CAVHS, Little Rock, Little Rock, AR 72202 (doc.ragesh@gmail.com) ACG Case Reports Journal / Volume acgcasereports.com Lavender et al Acute Liver Failure due to Miliary Liver Metastasis Figure Initial liver ultrasound showing (A) slightly heterogeneous echotexture without discrete masses Echogenic streaks were seen (narrow arrow), which are portal vein-parenchymal interfaces (indicate an acute hepatitis process) Follow-up ultrasound showing (B) innumerable subcentimetric hyperechoic nodules compatible with metastatic disease (largest denoted with a wide arrow) and bright streaks which represent portal vein-parenchymal interfaces (narrow arrow) a contraindication for OLT, and we did not pursue OLT further The patient’s family opted for comfort care and declined somatostatin receptor scintigraphy and chest CT We suspected a primary lung lesion but could not identify it DISCUSSION ALF from malignant infiltration is very uncommon, although the liver is the most common site for metastasis (36%) Liver metastasis is even more frequent with tumors arising from the portal vein drainage area (48%).3 In the series by Rich et al,1 16 (59.2%) in 27 cases represented a new diagnosis of malignancy In a study of 4,020 patients with ALF from the United Kingdom, infiltrative liver disease accounted for 18 cases and mostly resulted from malignancy including non-Hodgkin lymphoma (9 patients), Hodgkin disease (3 patients), metastatic carcinoma (4 patients), and hemophagocytic syndrome without a clear source (2 patients).2 ALF attributed to metastasis can occur because of (i) massive parenchymal infiltration leading to loss of critical functional liver mass, (ii) small bile duct infiltration leading to extensive cholangitis and bile duct necrosis, (iii) hepatic venous infiltration resulting in ischemic liver injury, (iv) massive sinusoidal infiltration by malignant cells leading to sudden ischemia and subsequent hepatocellular necrosis, and (v) cytokinemediated injury especially in lymphomas, leading to interlobular bile duct destruction and portal fibrosis, resulting in vanishing bile duct syndrome.4–7 Cytokine-mediated injury explains the disparity between minimal tumor load and extensive cholestasis seen with some cases of Hodgkin disease, where interleukin-2-mediated Kupffer cell activation causes further cytokine release and sinusoidal endothelial injury.3,7 As reported by Rowbotham et al,2 serum transaminase levels (median AST 358, range 78–768 IU/L) may not be very high compared with typical extreme elevation in noninfiltrative conditions leading to ALF Rich et al described higher transaminase levels (median AST of 963 IU/L [125–7,197], median ALT 673 IU/L [46–6,904]), which was surprising for tissue necrosis expected to occur with massive liver infiltration Most Figure Abdominal contrast-enhanced computed tomography showing diffuse liver enlargement with thrombosis of segment branch (white arrow) of the portal vein with patent left and main portal vein ACG Case Reports Journal / Volume acgcasereports.com Lavender et al Acute Liver Failure due to Miliary Liver Metastasis Figure Histopathology images of liver biopsy showing (A) benign hepatocytes interspersed with poorly differentiated small-cell carcinoma cells, (B) staining strongly positive for Ki67, and (C) synaptophysin, which are all suggestive of high-grade neuroendocrine carcinoma (magnification 203) of the reported cases of diffuse liver infiltration reveal a hepatocellular pattern of liver injury However, with progression of the disease, superimposed sepsis, bone marrow infiltration, and ineffective erythropoiesis may result in elevation of indirect bilirubin Massive infiltration of large bile ducts can occasionally result in an obstructive pattern of liver injury.2 Miliary metastases refer to metastatic lesions that are diffuse, innumerable, and small (usually less than cm).8 The rapid evolution of miliary pattern in radiological imaging within a week, as in our case, usually indicates infectious etiology (disseminated fungi or tuberculosis) or aggressive malignancies The miliary pattern of metastasis is usually seen with epidermal growth factor receptor mutation in non–small-cell lung carcinoma and E-cadherin mutations in breast carcinoma, resulting in diffuse spread of tumor cells instead of larger nodules.8,9 Facio et al10 had reported miliary liver metastasis from neuroendocrine carcinoma, identified during surgery that was missed in magnetic resonance, CT, and somatostatin receptor scintigraphy ALF due to malignancy usually has an extremely poor prognosis, typically resulting in death within to weeks.1,2 Treatment of ALF due to metastasis is usually restricted by inability to start chemotherapy in the setting of ALF There is no consensus on when to perform liver biopsy in ALF of indeterminate, but most recommendations suggest liver biopsy if an infiltrative etiology is suspected.11 To conclude, clinicians must keep a high index of suspicion while evaluating the etiology of ALF, and malignant infiltration should be ruled out if the initial workup is noncontributory Moderate elevation in transaminase levels, as opposed to extremely high values seen in most cases of ALF, could be indicative of infiltrative liver etiology Diffuse liver metastasis may not reveal mass lesions, and the initial abdominal imaging can be noncontributory Thus, close follow-up imaging and liver biopsy may be needed to clinch the diagnosis DISCLOSURES Author contributions: CA Lavender and J Stout wrote the manuscript H Chung provided the radiology images ACG Case Reports Journal / Volume M Johnson provided the pathology images RB Thandassery wrote the manuscript, approved the final version, and is the article guarantor Financial disclosure: None to report Informed consent could not be obtained from the family of the deceased All identifying information has been removed from this case report to protect patient privacy Received July 30, 2019; Accepted October 14, 2019 REFERENCES Rich NE, Sanders C, Hughes RS, et al Malignant infiltration of the liver presenting as acute liver failure Clin Gastroenterol Hepatol 2015;13(5): 1025–8 Rowbotham D, Wendon J, Williams R Acute liver failure secondary to hepatic infiltration: A single centre experience of 18 cases Gut 1998;42: 576–80 Willis RA The Spread of Tumours in the Human Body Butterworths: London, 1973 Zafrani ES, Leclercq B, Vernant JP, et al Massive blastic infiltration of the liver: A cause of fulminant hepatic failure Hepatology 1983;3:428–32 Dich NH, Goodman ZD, Klein MA Hepatic involvement in Hodgkin’s disease Clues to histologic diagnosis Cancer 1989;64:2121–6 Harrison HB, Middleton HM, Crosby JH, Dasher MN Fulminant hepatic failure: An unusual presentation of metastatic liver disease Gastroenterology 1981;80:820–5 Woolf GM, Vierling JM Disappearing intrahepatic bile ducts: The syndromes and their mechanisms Semin Liver Dis 1993;13:261–75 Hsu F, Nichol A, Toriumi T, De Caluwe A Miliary metastases are associated with epidermal growth factor receptor mutations in nonsmall cell lung cancer: A population-based study Acta Oncol 2017; 56(9):1175–80 Hirohashi S Inactivation of the E-cadherin-mediated cell adhesion system in human cancers Am J Pathol 1998;153(2):333–9 10 Fazio N, Di Meglio G, Lorizzo K, de Brand F Miliary hepatic metastases from neuroendocrine carcinoma Dig Surg 2008;25:330 11 Wendon J, Cordoba J, Wendon J, et al EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure J Hepatol 2017;66(5): 1047–81 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not 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Volume acgcasereports.com Lavender et al Acute Liver Failure due to Miliary Liver Metastasis Figure Histopathology images of liver biopsy showing (A) benign hepatocytes interspersed with poorly differentiated...Lavender et al Acute Liver Failure due to Miliary Liver Metastasis Figure Initial liver ultrasound showing (A) slightly heterogeneous echotexture... had reported miliary liver metastasis from neuroendocrine carcinoma, identified during surgery that was missed in magnetic resonance, CT, and somatostatin receptor scintigraphy ALF due to malignancy