P. Szturz 1; J. Kyclová 2; M. Moulis 2; M. Navrátil 1; Z. Adam 1; J. Vanicek 3,4; J. Mayer 1
Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Masaryk University, School of Medicine, Czech Republic
1; Institute of Pathology, University Hospital Brno and Masaryk University, School of Medicine, Czech Republic
2; Department of Imaging Methods, Masaryk University, School of Medicine, Czech Republic
3; International Clinical Research Center – Department of Imaging Methods, St. Anne‘s University Hospital Brno, Czech Republic
Klin Onkol 2013; 26(1): 49-52
Tato publikace byla připravena v rámci aktivity následujících grantů: MUNI/A/0723/2012 a FNUSA-ICRC (No.CZ.1.05/1.1.00/02.0123).
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Obdrženo: 2. 9. 2012
Přijato: 30. 1. 2013
Background: Spontaneous hepatic bleeding is a rare but potentially life-threatening complication of primary systemic amyloidosis. Although the liver is a common site of amyloid deposition, clinical presentation is usually mild or absent.
Case: We report a case of a female patient, who had been repeatedly surgically revised because of liver rupture and hemoperitoneum. Initially, the computed tomography finding was interpreted as liver hemangioma. However, based on liver biopsy, the diagnosis had to be changed to primary systemic amyloidosis, and the patient was referred to our hematooncology department. Due to a considerably advanced disease, the patient was eligible only for palliative chemotherapy with cyclophosphamide and dexamethasone, which could not deflect the course of rapidly progressing liver destruction.
Conclusion: The cause behind ruptured and bleeding liver does not always need to be hemangioma but rather amyloidosis. In cases of advanced disease and in patients with contraindications for aggressive treatment, the outlook for complete hematological and organ treatment response is very limited. An early diagnosis is of utmost importance. Although liver biopsy brings the definite results, screening for monoclonal protein in serum or urine, leading to a search for AL amyloidosis, may be sufficient for diagnosis. The presence of some of the warning signs (B-symptoms such as fevers or subfebrile temperatures, fatigue, weight loss; and paraneoplastic laboratory findings such as elevated C-reactive protein and erythrocyte sedimentation rate) should raise suspicion of a lymphoproliferative disease.
Primary systemic (immunoglobulin light chain, AL) amyloidosis belongs to a group of protein misfolding disorders characterized by deposition of insoluble fibrils in the extracellular matrix . Other forms of systemic amyloidosis include reactive, β2-microglobulin and hereditary such as transthyretin, fibrinogen or lysozyme amyloidoses [2–4]. In patients with AL variant, the amyloidogenic protein is derived from monoclonal light chains. Although the liver is a common site of amyloid deposition, clinically significant deteriorations of hepatic functions are rare and reports on spontaneous liver bleeding are exceptional .
Herein we report on the case of a woman diagnosed with an aggressive form of primary systemic amyloidosis with predominant liver involvement. Initially, the CT finding was interpreted as atypical liver hemangioma and the patient was repeatedly surgically revised because of liver rupture and hemoperitoneum.
In 2008, a 58-year-old woman presented with dyspeptic symptoms, fatigue and subfebrile temperatures. Her past medical history included arterial hypertension, chronic antral gastritis, large intestine diverticulosis, cholecystectomy and intervertebral disc surgery. Laboratory tests showed gamma-glutamyltransferase (GGT = 261.6 U/L, upper limit for GGT = 36 U/L) and erythrocyte sedimentation rate (22 mm/h and 49 mm/2 h) elevations. Magnetic resonance imaging and computed tomography (CT) of the abdomen displayed only a mild lymphadenopathy near the truncus coeliacus without any explanatory results.
In April 2009 however, a restaging CT examination revealed a large oval hemangioma-like infiltrate, 10 × 6 cm in size, in the left liver lobe. A cytological evaluation of liver aspirate was roughly compatible with the radiologically suspected diagnosis of hemangioma. The patient was then indicated for superselective embolization of the left hepatic artery branch supplying the infiltration expanding rapidly as seen on a series of ultrasound examinations. By that time, GGT further increased to 580.8 U/L, full blood count and coagulation parameters were within normal ranges. In one month after the procedure, the patient was acutely admitted to hospital and repeatedly surgically revised because of hemoperitoneum. The source of the bleeding was apparent on a CT exam as a 10 cm long laceration of the right liver lobe (Fig. 1). Following the surgical stabilization, gradual liquefaction and regression of the residual subhepatal hematoma were described on a series of ultrasound and CT investigations.
Nevertheless, the patient’s health status worsened and she was repeatedly hospitalized due to recurrent fevers, abdominal pains and weight loss of up to 20 kg in 6 months. Markedly elevated GGT (1354.2 U/L) and alkaline phosphatase (ALP = 2008.2 U/L, upper limit for ALP = 104.4 U/L) contrasted with normal transaminase and bilirubin levels. Increased C-reactive protein (CRP = 158.2 mg/L, upper limit for CRP = 5 mg/L) was evident. Magnetic resonance cholangiopancreatography didn’t find any biliary obstruction in the enlarged liver. Clinically rock hard liver with its lower border extending 10 cm below the costal margin was described and a CT scan showed diffuse inhomogeneous liver parenchyma with multiple new infiltrations.
Then, at a surgical clinic, the woman was indicated for a liver biopsy revealing lambda-AL amyloidosis and finally referred to our hematooncology department. In addition to monoclonal immunoglobulin G lambda spike (9.2 g/L), serum free kappa and lambda light chains were 27.3 mg/L (upper limit = 19.4 mg/L) and 113 mg/L (upper limit = 26.3 mg/L), respectively. Echocardiography identified amyloid heart disease and proteinuria signaling nephropathy was observed (2.75 g per 24 hours, including urine paraprotein). Renal ultrasound did not notice any pathological changes, no electrocardiographic abnormalities were described either. Due to the overall condition of the patient and advanced state of the disease with progressive hepatomegaly and formation of new subcapsular and intraparenchymal hematomas (maximum 16 × 6 cm in size), aggressive chemotherapy and liver or hematopoietic stem cell transplantations were contraindicated. The patient was started on low-intensity palliative chemotherapy with cyclophosphamide and dexamethasone.
The aggressivity of the disease was expressed by hypoalbuminemia (ALB = 25 g/L, lower limit for ALB = 34 g/L), elevations of β2-microglobulin (β2-m = 6.46 mg/L, upper level for β2-m = 2.4 mg/L) and lactate dehydrogenase (LD = 808.8 U/L, upper limit for LD = 213 U/L) with physiological serum creatinine concentration and absence of hemolysis. The cholesterol level was increased (CH = 294 mg/dL, upper level for CH = 193 mg/dL). Two more episodes of hemoperitoneum had occurred in this patient (June 2010 and October 2010) and the woman died of multiorgan failure in November 2010. Autopsy showed AL amyloidosis with massive infiltration of the liver (weight 3,820 g), myocardium, spleen (sago spleen), kidneys, intraabdominal lymph nodes and suprarenal glands. Microscopic amyloid depositions were found in the bone marrow, lung interstitium, gastric mucosa, tongue and thyroid gland. The liver was extremely fragile and disintegrating at a touch (Fig. 2).
AL amyloidosis is a clonal disorder of plasma cells producing monoclonal light chains with a potential to aggregate and deposit in bundles of insoluble ß-sheet fibrillar protein . Small populations of pathological plasma cells are found in the bone marrow and/or in the spleen. The diversity of clinical manifestations is related to continuous amyloid protein depositions in a wide variety of tissues leading to multisystem organ dysfunction. Clonal immunoglobulin variable region genes play a particular role in the organ tropism . Most commonly involved are the kidney, heart, nervous system and gastrointestinal tract .
Although liver affection represents a common histological finding and hepatomegaly occurs in about 80% of the cases, clinical presentation is usually mild or absent. Laboratory tests typically reveal proteinuria, hypercholesterolemia and ALP elevation. In addition, higher ALP levels and CRP levels were shown to indicate liver involvement in patients with AL amyloidosis. Other biochemical liver test abnormalities are inconsistent and tend to appear in the advanced disease [4,7]. The following clues were found to indicate the presence of hepatic amyloidosis: (1) proteinuria, (2) serum monoclonal protein with hepatomegaly and/or ALP elevation, (3) Howell-Jolly bodies in the peripheral blood smear [8,9].
Rare complications of hepatic amyloidosis include cholestatic jaundice, ascites, hepatorenal syndrome, portal hypertension or even hepatic failure [4,7,10]. Descriptions of spontaneous hepatic rupture due to amyloid deposition are mostly limited to single cases [3,11–23] or small series reports [2,24]. Although being almost always fatal, successful surgical interventions [17,24], transcatheter hepatic artery embolizations [16,17] and even emergency liver transplantation [20,21] have been reported. Tam et al described a catastrophic course of high-dose melphalan and autologous stem cell transplantation in AL amyloidosis complicated by a spontaneous liver rupture . Not only may patients with AL amyloidosis be affected, but also these with multiple myeloma-associated amyloidosis [18,23], hereditary lysozyme amyloidosis [2,20,21] and hereditary transthyretin amyloidosis .
The median survival for patients with primary systemic amyloidosis is about 20 months . Hepatic involvement represents a poor prognostic factor decreasing the median survival to only 9 months . Various treatment options have been proposed including melphalan, prednisone, colchicine, dimethyl sulfoxide, autologous peripheral blood stem cell transplantation following high dose chemotherapy and newly also bortezomib [25,26]. The aim of treatment is to eradicate the monoclonal B-cell population leading to cessation of amyloid deposition and its resorption, which in turn may improve organ functions . The median time to organ response is 4 months [26,27]. The therapeutic outcome depends on the degree of monoclonal protein reduction, achieving complete remission results in significantly higher portion of improved amyloid-related organ disease . Therefore, while being limited by their toxicity in medically-compromised patients, aggressive modalities represented by stem cell transplantation bring the most promising results.
In our patient, the disease was disclosed in its late-stage, when the liver was irreversibly destructed. Due to the patient’s poor performance status and extensive affection of other vital organs, including cardiomyopathy and nephropathy, liver transplantation was contraindicated. The systemic chemotherapy had only a palliative intent. In terms of time, the potential organ treatment response lay beyond the prognostic expectancy of a rapidly progressing oncological disease.
In conclusion, the cause behind ruptured and bleeding liver doesn’t always need to be a hemangioma but also amyloidosis may be the case. In cases of advanced disease and in patients with contraindications for aggressive treatment, the outlook for a complete hematological and organ treatment response is very limited. Therefore, an early diagnosis is of utmost importance. Although a liver biopsy brings the definite results, screening for monoclonal protein in serum or urine, leading to a search for AL amyloidosis, may be sufficient for the diagnosis. The presence of some of the warning signs (B-symptoms such as fevers or subfebrile temperatures, fatigue, weight loss; and paraneoplastic laboratory findings such as elevated acute-phase markers) should raise suspicion of a lymphoproliferative disease [29–31].
This publication was prepared as part of the MUNI/A/0723/2012 project as well as it is a part of activities within the European Regional Development Fund-Project FNUSA-ICRC (No.CZ.1.05/1.1.00/02.0123).
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Petr Szturz, MD, Ph.D
Department of Internal Medicine, Hematology and Oncology
University Hospital Brno
625 00 Brno
Submitted: 2. 9. 2012
Accepted: 30. 1. 2013
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Paediatric clinical oncology