Indian Journal for the Practising Doctor

h4>Yasser M Bhat, Sabba Maqbool

ISBN: 0973-516X

Yasser M. Bhat, MD, is from the Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Sabba Maqbool, MD, is from the Department of Gastroenterology, Hepatology and Nutrition, Temple University, Philadelphia, PA

Correspondence: Yasser M. Bhat, MD, Department of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, 200 Lothrop Street, C-Wing/PUH, Mezzanine level, Pittsburgh, PA 15213.
bhatym@upmc.edu

Abstract

Acute liver failure due to hepatic involvement by hematological malignancies is very rare, even though these malignancies frequently affect the liver. We present a case of a young male who presented with flu-like illness and jaundice that rapidly progressed to acute liver failure. A diagnosis of massive infiltration of the liver by a malignancy of hematolymphoid origin was made. His condition deteriorated rapidly and he died 12 days after admission. Hematopoietic malignancy as a cause of acute liver failure should be considered in cases without apparent etiology especially if associated with lactic acidosis and hepatomegaly. This disease carries an extremely poor prognosis and rapidly fatal outcome unless recognized and treated early. Liver biopsy is an invaluable tool in this quest and helps immensely to make an early diagnosis while excluding other etiologies of acute liver failure.

Keywords: acute liver failure, infiltrative hemato-lymphoid malignancy.

Introduction

The liver is a very common site for metastasis of tumors with some suggesting hepatic involvement in 36% of all deaths due to cancer¹. In spite of this, liver dysfunction as a result of cancer involvement is rare until the terminal stage of the illness². There are sporadic case reports describing the occurrence of acute liver failure (ALF) due to malignant infiltration of the liver as the initial manifestation of disease. Hematologic malignancies are the commonest among them, including Hodgkin’s disease^3,4, non-Hodgkin’s lymphoma^5-9, malignant histiocytosis^10-12 and acute and chronic leukemia^13-15. Even rarer cause is any other infiltrative disease such as adenocarcinoma, melanoma and metastatic anaplastic tumors^16-22.

Fulminant hepatic failure is defined as significant liver dysfunction, with synthetic dysfunction and encephalopathy, developing within 8 weeks of the onset of symptoms, in the absence of preexisting liver disease^18,23-27. There are approximately 2000 cases of ALF yearly in the United States with an overall mortality of 80%^23,27. It is a severe condition associated with many diseases, most commonly viral and drug induced hepatitis^23,24. Less common causes include toxins (carbon tetrachloride, Amanita), vascular events (hepatic ischemia, venoocclusive disease, heatstroke), Wilson’s disease, Reyes syndrome and acute fatty liver of pregnancy²³. It is rarely associated with infiltrative malignancies and even less likely to be the presenting feature in these cases^6,9.

We present here a case of malignant infiltration of the liver presenting as ALF followed by rapid deterioration and death. This rare disease is reviewed to emphasize the value of early detection and treatment as the only hope for cure.

Case Report

A 40-year-old white male presented to the emergency room with complaints of abdominal discomfort and distension for the last five days. This was accompanied by mild fatigue and lethargy, decreased appetite, tea-coloured urine and pale stools. He had been on vacation in Virginia Beach when these symptoms started but reported no nausea, vomiting, diarrhea or intake of any uncooked food, including mushrooms. A complete review of symptoms was only significant for occasional gingival bleeding over the last 3 months. He had no prior medical illnesses and was on no medications. He worked as a landscaper and consumed 3-4 alcoholic drinks (beer) per day. He denied any tobacco use. On admission the patient appeared ill and fatigued but was fully alert and oriented. Body temperature and blood pressure were normal, heart rate was 110 beats/min and oxygen saturation was 96% on room air. He had mild jaundice with icteric sclerae. He had no asterexis. Lung exam was normal as were the heart sounds. Abdomen was distended with moderate ascites. Liver was enlarged and palpable 3 cm below the costal margin. The spleen was moderately enlarged. Rectal examination was normal.

Fig 1: CT scan of the abdomen with intravenous contrast showing marked hepatomegaly and lymphadenopathy in the porta hepatis and massive splenomegaly with peripheral wedge shaped infarcts.

Initial laboratory data revealed severe electrolyte abnormalities and lactic acidosis (serum sodium 124 mmol/L, potassium 6.5 mmol/L, carbon dioxide 11 mmol/L, anion gap 22, calcium 6.4 mg/dl, phosphorous 6.8 mmol/L, lactate 6.1 mmol/L, arterial pH 7.27), renal failure (BUN 53 mg/dl, creatinine 3.0 mg/dl), severe hypoglycemia (initial blood sugar 9.0 mg/dl that responded well to IV glucose) and hepatic abnormality (total bilirubin 4.4 mg/dl, conjugated bilirubin 3.3 mg/dl, ALT 1048 IU/L, AST 2757 IU/L, alkaline phosphatase 218 IU/L, albumin 2.1 g/dl). Complete blood counts showed leukocyte count of 5.1×109/L (82% neutrophils, 16% bands and 1% lymphocytes), hemoglobin of 8.8 gm/dl and platelet count of 31 x 109/L. Severe coagulopathy was noted with prothrombin time 66 sec, international normalized ratio 5.5 and partial thromboplastin time of 56 sec. Chest radiograph and urine analyses were normal. An initial electrocardiogram showed peaked T-waves consistent with the hyperkalemia.

He was admitted to the intensive care unit and a liver transplant evaluation was initiated. He was treated with intravenous fluids, empiric antibiotics (pipercillin-tazobactam, acyclovir and diflucan), fresh frozen plasma and platelet transfusions. Further laboratory investigations including hepatitis, Epstein-Barr virus, Herpes simplex virus, cytomegalovirus and human immunodeficiency virus serologies were normal. Acetaminophen level, iron profile, alpha-1 antitrypsin levels, ceruloplasmin, serum copper and autoimmune markers were all normal. Serum lactate dehydrogenase was elevated at 970. Peripheral blood smear showed no atypical cells or schistocytes. A right upper quadrant ultrasound revealed an enlarged liver and spleen but patent hepatic vasculature and biliary ducts. A computed tomography scan of the abdomen and pelvis showed massive splenomegaly with multiple low density wedgeshaped peripheral lesions, marked hepatomegaly with lymphadenopathy in the porta hepatic and retro-peritoneal lymphadenopathy (Figure 1).

The patient developed stage 2 hepatic encephalopathy on day two and was intubated and placed on mechanical ventilation. Due to the coaguolapathy, a transjugular liver biopsy was performed. The liver biopsy revealed submassive hepatic necrosis (40-50% of the hepatic parenchyma was necrotic) (Figure 2A).

Fig 2: (A) The liver biopsy shows areas of extensive necrosis. The right side of the picture demonstrates a zone of coagulative (ischemic-type) necrosis while the left side of the picture shows viable hepatocytes with microvesicular steatosis (hematoxylin and eosin, 100x).
(B) Several large atypical mononuclear cells (arrows) are present in and around the lumen of a central vein (hematoxylin and eosin, 200x).
(C) The atypical mononuclear cells (here present within the liver sinusoids) are strongly and diffusely positive for CD45 (brown stain) (CD45 immunohistochemical stain, 100x).

Fig 3: Histologic examination of the hypercellular bone marrow biopsy reveals numerous atypical large cells with prominent nucleoli and irregular nuclear contours. These neoplastic cells are positive for CD45 and bcl-2 immunohistochemical stains (not shown). The scattered smaller cells with hyperchromatic nuclei that are also noted in this figure represent residual normal hematopoietic elements in the bone marrow.

Histologic & Immunohistologic Features

A subtle atypical mononuclear infiltrate was noted around the central veins (Figure 2B) and within the sinusoids (Figure 2C). Immunohistochemistry was performed on the liver biopsy. The atypical mononuclear infiltrate was composed of CD45 (leukocyte common antigen) positive cells (Figure 1C), but these cells were negative for B-cell markers (CD20, CD79a), T-cell markers (CD2, CD3, CD5, CD7), other lymphoid and natural killer cell markers (CD56, TIA-1, Granzyme-B, TdT) and myeloid markers (CD34, myeloperoxidase) (not shown). Weak and possible nonspecific staining was observed with CD43, CD68 and lysozyme (not shown). A bone marrow biopsy was subsequently performed and showed involvement by an atypical mononuclear cell infiltrate, similar to the infiltrate seen in the liver. In the bone marrow, the cellular detail was better preserved (Figure 3).

Immunohistochemical stains performed on the bone marrow biopsy showed identical immunophenotype; an additional stain performed on the bone marrow biopsy, bcl-6, was positive, which suggested a lymphoid origin (not shown). Hodgkin lymphoma was excluded based on the staining for CD45 (LCA) and the morphologic appearance of the malignant cells. The fact that the lineage of this hematolymphoid neoplasm could not be determined by immunohistochemistry is very unusual.

Although flow cytometry was performed on the bone marrow, it failed to characterize the neoplastic cells, possibly due to sampling error. Cytogenetic analysis revealed a normal male karyotype. Based on the pathologic analysis, the liver, bone marrow and peripheral blood were involved by a hematolymphoid neoplasm, not further classified, but with a suggestion of a lymphoid origin.

The patient was not considered a transplant candidate due to his malignancy. His condition continued to worsen and he passed away 12 days after admission from ALF. At autopsy, he had massive hepatosplenomegaly, with a liver weight of 3,430 grams (normal, 1,200-1,500 grams) and spleen weight of 2,000 grams (normal, 150 grams); both organs showed massive necrosis and infiltration by the hematolymphoid malignancy. The hepatic hilar lymph nodes were also massively enlarged and replaced by the hematolymphoid malignancy.

Discussion

Lymphoma is defined as a malignant neoplastic process of lymphoid tissue and is classified into two different categories – Hodgkin’s disease and non-Hodgkin’s lymphoma. Approximately 30,000-50,000 cases of non- Hodgkin’s lymphoma occur annually making it the sixth most common malignancy in the United States^27,28. In India, the prevalence is estimated to be less than that in the US but more than that among the Chinese. When treated, Non-Hodgkin’s disease has a 50% 5-yr survival rate and median survival of 8 months²⁸.

Hodgkin’s disease carries a better prognosis with a 90% 5-yr survival in stage I and II with treatment in and 75% with advanced stages28. Hepatic involvement has been described in 16%- 22% cases of non-Hodgkin’s lymphoma^5,9,29. Significant hepatic dysfunction is these cases is uncommon⁹. Rarely, lymphoma can result in ALF and less than 40 cases have been described. This occurs when the hepatic parenchyma is massively replaced by tumour cells with diffuse intrasinusoidal propagation. This infiltration can result in hepatic ischemia due to massive sinusoidal infiltration or tumor cell replacement of the hepatic parenchyma^14,17,18,27.

A large review by Rowbotham et al²⁹ showed that only 18 of 4,020 patients admitted to a specialized liver unit over 18 years had ALF due to malignant infiltration. The etiology was non-Hodgkin’s lymphoma in nine cases, Hodgkin’s disease in three, infiltrative metastatic carcinoma in four and hemophagocytosis in two. Mean age was 40.7 years and prodromal symptoms, though nonspecific, occurred two to four weeks before onset of ALF. The course was of rapid deterioration and death occurred in most cases from multiorgan failure. The diagnosis was made ante mortem in 15 patients with the aid of liver biopsy in seven patients, bone marrow biopsy in five, lymph node biopsy in two and ultrasound in one. Only one patient survived – he received appropriate chemotherapy for non- Hodgkin’s lymphoma diagnosed on liver biopsy.

Lettieri et al²⁷ published a case series of five patients with ALF due to infiltrative disease including two cases due to HTLV-1 associated adult T-cell leukemia/lymphoma – a novel observation. In addition, their review of thirty cases of ALF due to lymphoma revealed some common clinical features such as: 1) evidence of bone marrow, lymph node or splenic involvement; 2) elevated liver enzymes and bilirubin; 3) lactic acidosis; 4) massive infiltration of the liver and other organs as a major finding and 5) rapidly fatal outcome. Lymphoma presenting as ALF was seen twice as often in men (20 out of 30) with average age of 48.6 years^14,27. Mortality was 83% with an average survival of 10.7 days. Chemotherapyinduced remission has been reported in 3 of 23 (13%) cases with non-Hodgkin’s lymphoma and 2 of 7 with Hodgkin’s disease (29%). No unique clinical features were identified in survivors and in 80% of the survival cases, the diagnosis was made on liver biopsy.

ALF as the initial manifestation of acute leukemia is exceedingly rare and usually carries a poor prognosis. It usually occurs in children and presents with indicators of high cell turnover such as elevated uric acid level and lactate dehydrogenase. Accompanying these may be a prodromal syndrome, elevated peripheral white cell count and hyperlactemia. A Medline search of ALF due to acute leukemia showed about 10 cases in published literature with a universally poor prognosis^14,30-36.

Clinical features of ALF become apparent when a large portion of the hepatocytes become necrosed18. Impaired gluconeogenesis with significant hypoglycemia, severe coagulopathy and lactic acidosis are hallmarks of synthetic dysfunction and were all apparent in our patient. Lactic acidosis results due to excessive lactate production, peripheral microvascular shunting and tissue hypoxemia and impaired metabolism by the liver^6,9,10,14,27.

In cases of ALF secondary to haematological malignancy, the commonest pathological finding is malignant infiltration into the hepatic parenchyma, vasculature or intrahepatic biliary tree with widespread hepatocellular necrosis37. Survival in ALF due to any cause is low. ALF due to acute hepatitis A carries the lowest mortality (35-55%), followed by acetaminophen toxicity (47-66%), hepatitis B (61-77%), drug reactions (86%) and non-A, non-B hepatitis (91%)^5,23,27. Patients with ALF not responding to therapy are referred for liver transplantation. In patients with lymphoma and ALF, the disease recurs rapidly and no mortality benefits have been observed. Therefore, liver transplantation is contraindicated in patients with lymphoma and must be excluded.

ALF as a presenting feature of a hematolymphoid malignancy is extremely rare and therefore not usually considered in the differential diagnosis. The diagnosis was made ante mortem in only about 50% of the cases²⁹. Establishing this diagnosis can be very difficult and requires a high index of suspicion. Given the poor prognosis, it should be considered in any patient presenting with ALF especially if associated with lactic acidosis, hepatomegaly and without an obvious etiology. Liver biopsy is crucial to the process of early diagnosis and initiating chemotherapy, which may be lifesaving.

The mortality for these procedures is less than 0.1% and if the coagulation abnormalities preclude the performance of a percutaneous liver biopsy, the transjugular method should be used. In conclusion, this is a rare disease with a fatal outcome. All cases of acute liver failure should be referred to a liver transplant center.

The role of liver biopsy cannot be overemphasized and it is crucial to establish an early diagnosis and initiate treatment – the only hope for cure.

References

1. Willis RA. The spread of tumors in the human body London: Butterworths; 1973.
2. Cello JP, Grendell JH. The liver in systemic conditions Philadelphia: WB Saunders; 1990. (Zakim D BT, ed. Hepatology. A Textbook of liver Disease.)
3. Trewby PN, Portmann B, Brinkley DM, Williams R. Liver disease as presenting manifestation of Hodgkin’s disease. The Quart J Med 1979;48(189):137-150.
4. Lefkowitch JH, Falkow S, Whitlock RT. Hepatic Hodgkin’s disease simulating cholestatic hepatitis with liver failure. Arch Pathol Lab Med. 1985;109(5):424-426.
5. Braude S, Gimson AE, Portmann B, Williams R. Fulminant hepatic failure in non-Hodgkin’s lymphoma. Postgrad Med J 1982;58(679):301-304.
6. Ghosh P, Fox IJ, Rader AM, Sorrell MF. Fulminant hepatic failure as the initial manifestation of non-Hodgkins lymphoma. Am J Gastroenterol 1995;90(12):2207- 2209.
7. Woolf GM, Petrovic LM, Rojter SE, et al. Acute liver failure due to lymphoma. A diagnostic concern when considering liver transplantation. Diges Dis Scien 1994;39(6):1351-1358.
8. Gargot D, Maitre F, Causse X. Primary liver Non-Hodgkin’s lymphoma presenting as fulminant hepatic disease. Euro J Gastroenterol Hepatol 1994(6):843-6.
9. Salo J, Nomdedeu B, Bruguera M, et al. Acute liver failure due to non-Hodgkin’s lymphoma. American J Gastroenterol 1993;88(5):774-776.
10. Colby TV, LaBrecque DR. Lymphoreticular malignancy presenting as fulminant hepatic disease. Gastroenterol 1982;82(2):339-345.
11. Crotty CP, Winkelmann RK. Cytophagic histiocytic panniculitis with fever, cytopenia, liver failure, and terminal hemorrhagic diathesis. J Am Acad Dermatol 1981;4(2):181-194.
12. Beaugrand M, Trinchet JC, Callard P, Ferrier JP. Malignant histocytosis presenting as a fulminant hepatic disease. Gastroenterol 1983;84(2):447-448.
13. Hess CE, Joyce RA. Acute myeloblastic leukemia presenting as progressive hepatic failure. Southern Med J 1981;74(8):1028- 1029.
14. Zafrani ES, Leclercq B, Vernant JP, Pinaudeau Y, Chomette G, Dhumeaux D. Massive blastic infiltration of the liver: a cause of fulminant hepatic failure. Hepatol (Baltimore, Md.). 1983;3(3):428-432.
15. Greer JP, Cousar JB, Miller RF, et al. T4+ (helper phenotype) chronic lymphocytic leukemia: case report with liver failure and literature review. Med Pediat Oncology. 1988;16(5):356-362.
16. Eras P, Sherlock P. Hepatic coma secondary to metastatic liver disease. Ann Internal Med 1971;74(4):581-583.
17. Harrison HB, Middleton HM, 3rd, Crosby JH, Dasher MN, Jr. Fulminant hepatic failure: an unusual presentation of metastatic liver disease. Gastroenterol 1981;80(4):820-825.
18. Myszor MF, Record CO. Primary and secondary malignant disease of the liver and fulminant hepatic failure. J Clin Gastroenterol 1990;12(4):441-446.
19. Krauss EA, Ludwig PW, Sumner HW. Metastatic carcinoma presenting as fulminant hepatic failure. Am J Gastroenterol 1979;72(6):651-654.
20. Nouel O, Bernuau J, Lebrec D, Laraki R, Rueff B, Benhamou JP. Severe hepatic failure and portal hypertension due to metastatic carcinoma of the liver (author’s transl). Gastroenterol Clin Et Biolog. 1979;3(2):135-137.
21. Bouloux PM, Scott RJ, Goligher JE, Kindell C. Fulminant hepatic failure secondary to diffuse liver infiltration by melanoma. J Roy Soc Med 1986;79(5):302-303.
22. Stein AM, Fawaz K, Tabrizi A, Blanchard R, Hou S. Multifocal malignant hemangioendothelioma presenting as acute hepatitis. A clinicopathologic study. Am J Gastroenterol 1977;67(4):370-374.
23. Lee WM. Acute liver failure. N Engl J Med 1993;329(25):1862-1872.
24. Riordan SM, Williams R. Fulminant hepatic failure. Clinics In Liver Disease. 2000;4(1):25-45.
25. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439-445.
26. Trey C, Davidson CS. The management of fulminant hepatic failure. Progress In Liver Diseases. 1970;3:282-298.
27. Lettieri CJ, Berg BW. Clinical features of Non-Hodgkins lymphoma presenting with acute liver failure: a report of five cases and review of published experience. The American Journal of Gastroenterology. 2003;98(7):1641-1646.
28. Aisenberg AC. Coherent view of non- Hodgkin’s lymphoma. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical Oncology. 1995;13(10):2656-2675.
29. Rowbotham D, Wendon J, Williams R. Acute liver failure secondary to hepatic infiltration: a single centre experience of 18 cases. Gut. 1998;42(4):576-580.
30. Anderson SH, Richardson P, Wendon J, Pagliuca A, Portmann B. Acute liver failure as the initial manifestation of acute leukaemia. Liver. 2001;21(4):287-292.
31. Felice MS, Hammermuller E, De Davila MT, et al. Acute lymphoblastic leukemia presenting as acute hepatic failure in childhood. Leukemia & Lymphoma. 2000;38(5-6):633-637.
32. Souto P, Romaozinho JM, Figueiredo P, et al. Severe acute liver failure as the initial manifestation of haematological malignancy. European Journal Of Gastroenterology & Hepatology. 1997;9(11):1113-1115.
33. Shehab TM, Kaminski MS, Lok AS. Acute liver failure due to hepatic involvement by hematologic malignancy. Digestive Diseases And Sciences. 1997;42(7):1400-1405.
34. Devictor D, Tahiri C, Fabre M, Mielot F, Dussaix E. Early pre-B acute lymphoblastic leukemia presenting as fulminant liver failure. Journal Of Pediatric Gastroenterology And Nutrition. 1996;22(1):103-106.
35. Conway EE, Jr, Santorineou M, Mitsudo S. Fulminant hepatic failure in a child with acute lymphoblastic leukemia. Journal Of Pediatric Gastroenterology And Nutrition. 1992;15(2):194-197.
36. McCord RG, Gilbert EF, Joo PJ. Acute leukemia presenting as jaundice with acute liver failure. Clinical Pediatrics. 1973;12(12):17A passim.
37. Woolf GM, Vierling JM. Disappearing intrahepatic bile ducts: the syndromes and their mechanisms. Seminars In Liver Disease. 1993;13(3):261-275.
38. Blakolmer K, Gaulard P, Mannhalter C, et al. Unusual peripheral T cell lymphoma presenting as acute liver failure and reappearing in the liver allograft. Transplantation. 2000;70(12):1802-1805.
39. Thompson DR, Faust TW, Stone MJ, Polter DE. Hepatic failure as the presenting manifestation of malignant lymphoma. Clinical Lymphoma. 2001;2(2):123-128.