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Systemic amyloidosis of amyloid light chain associated protein (AL), also called primary amyloidosis, frequently involves the liver, but rarely causes clinically apparent liver disease. The more common presentation is with acute renal failure. Hepatomegaly and mild elevation of alkaline phosphatase are the most common clinical and biochemical findings, respectively. We report a case of systemic amyloidosis of AL that clinically presented as acute-on-chronic liver failure and resulted in a fatal clinical course in a 56-year-old man.
Hepatic involvement in systemic amyloidosis is common and occurs in myeloma-related (AL) amyloidosis (primary) and amyloid-associated (AA) amyloidosis (secondary or reactive). Significant clinical evidence of hepatic dysfunction is usually subclinical and may include hepatomegaly, mild jaundice, and, rarely, severe cholestasis.1 Portal hypertension may complicate hepatic amyloidosis, and subcapsular hematoma and spontaneous rupture of liver have been reported.2 Acute and fulminant liver failures have only been described for AL amyloidosis in the setting of myeloma.3 A diagnosis of AL amyloidosis (primary hepatic amyloidosis) with progressive liver failure is rarely seen in the absence of myeloma, with few prior cases of primary amyloidosis presenting as acute liver failure in the reviewed literature.4-10 The diagnostic challenge in this case now serves as a differential in the etiological work-up for progressive liver failure.
A previously healthy 56-year-old man presented with progressive jaundice for 6 weeks and abdominal distension with swelling of feet for 4 weeks. He also had symptoms of fatigue and mild generalized itching. His past medical history was unremarkable, with no prior history of liver disease. On physical examination, he was deeply icteric, had bilateral pitting lower-limb edema, a left-sided pleural effusion, a short apical systolic murmur, and a flapping tremor. His abdominal examination revealed massive hepatosplenomegaly with moderate ascites. His clinical presentation was akin to acute-on-chronic liver failure (ACLF) with the appearance of ascites and encephalopathy within 2 weeks of presentation with jaundice. His primary physician referred the case to our center after he developed signs of liver decompensation. Hence his initial diagnostic work-up focused on identifying the underlying etiology. Complete blood count and serum electrolytes were within normal limits. Laboratory studies showed blood urea 45 mg/dL, creatinine 0.9 mg/dL, total bilirubin 22 mg/dL, serum albumin 24g/L, international normalized ratio 3.2, alkaline phosphatase 1,496 IU/L, γ-glutamyltransferase 136 IU/L, alanine aminotransferase 128IU/L, and aspartate aminotransferase 170IU/L. C-reactive protein was elevated, and immunoglobulin (Ig) levels were normal with IgG 12 g/L, IgA 3.15g/L, and IgM 0.52g/L. Serum protein electrophoresis and β2 microglobulin were within normal limits, and urinalysis was negative for Bence-Jones proteinuria. Alpha-fetoprotein was within the normal range. Serologies for hepatitis were all unremarkable. Autoimmune work-up, including antinuclear, anti-smooth muscle, and anti-DNA antibodies, were negative. The 24-hour urinary protein excretion was 0.068g/L.
Abdominal ultrasonography revealed hepatosplenomegaly with no focal liver lesions and normal intra- and extrahepatic bile ducts. Computed tomography of the abdomen showed the liver measured 16.6-cm in craniocaudal span, with a subtle lobulated outline and widened interlobar fissures. The main portal vein was mildly dilated with thin collaterals, suggestive of portal hypertension. There was no evidence of retroperitoneal or mesenteric lymphadenopathy (Figure 1). Transthoracic echocardiography showed normal chambers with diastolic dysfunction, normal systolic function with ejection fraction of >60%, and no pericardial effusion. Ascitic fluid analysis showed 500 cells, 90% lymphocytes, high serum albumin ascitic gradient (2.1), low protein (2.4g/L), and low adenosine deaminase (5.7 IU/L). Polymerase chain reaction was negative for tuberculosis and there were no malignant cells on cytology. These findings were consistent with portal hypertension.
Transjugular liver biopsy was performed. Hepatic venous pressure gradient was 14 mm Hg, confirming the clinical diagnosis of portal hypertension. Liver biopsy showed near complete effacement of acinar architecture by sinusoidal and portal deposits of extracellular, pale eosinophilic, hyaline, amorphous, acellular material. Hepatocytes showed pressure atrophy and focal presence of canalicular bile. Portal tracts showed no significant inflammation with F1 fibrosis (Figure 2). The material stained positive with Congo red and displayed green birefringence when viewed under polarized light, confirming amyloid deposition. Stains for iron and copper deposition were not remarkable. Immunohistochemistry revealed that the amyloid deposits consisted largely of light chains, with λ being stronger than κ (Figure 3). Bone marrow aspiration showed erythroid hyperplasia with normoblastic to mild megaloblastic erythropoiesis. Plasma cells were 9%. No evidence of myeloma was seen. Serum free light chains were negative. Skeletal survey did not reveal any lytic lesions. Rectal biopsy showed maintained crypt architecture. There were focal deposits of acellular eosinophilic amorphous material in the wall of blood vessels in submucosa. These deposits also showed apple green birefringence on staining with Congo red under polarization. This confirmed extrahepatic deposition of amyloid (Figure 4).
The patient’s clinical condition rapidly deteriorated over the next few days, and he developed fulminant liver failure and sepsis. He could not be offered chemotherapy due to liver failure, and was deemed unfit for liver transplantation. He died within 12 days of presentation at our center.
Hepatic failure can present as acute liver failure, ACLF, or a chronic decompensation of an end-stage liver disease. ACLF has been defined by the Asian Pacific Association for the Study of the Liver (APASL) as an acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.10 Among the infectious etiologies, reactivation of hepatitis B virus infection, either spontaneously or due to intensive chemotherapy or immunosuppressive therapy, as well as acute hepatitis E virus infection and hepatitis C virus infection have been reported.11 Alcoholic hepatitis commonly causes decompensation of stable liver disease in various studies.11
Amyloidosis is a medical condition of abnormal protein metabolism, characterized by extracellular deposition of misfolded, normally soluble proteins and polypeptides in fibrillary form. Amyloidosis is classified on the basis of the chemical composition of the amyloid fibrils and their precursor protein to morphologically identical but chemically different types. There are two principal types of amyloidosis. The first is AL amyloidosis, which is associated with plasma cell dyscrasias and malignant B-cell-type lymphoproliferative malignancies and is characterized by the deposition of the variable region of the immunoglobulin κ or λ light chains. The second is AA amyloidosis, which is associated with chronic infectious and noninfectious inflammatory conditions, Hodgkin lymphoma, and non-lymphoid malignancies and is characterized by the deposition of amyloid A fibrils, which are derived from the serum AA precursor protein. Both types can be localized or systemic.1
Multiple myeloma is the second most common hematologic malignancy (13%) and constitutes 1% of all cancers. AL amyloidosis arises from diseases with disordered immune cell function, such as multiple myeloma and other immunocyte dyscrasias, and it is the most common form of systemic amyloidosis. Liver involvement is less common in myeloma (32%) when compared with chronic leukemia (80–100%), myeloproliferative diseases, acute leukemia (60–70%), and non-Hodgkin lymphoma (50–60%).12
Although the liver may demonstrate amyloid deposits, AL amyloidosis is not associated with significant liver dysfunction.13 A recent study determined that only 0.44% of cases with liver failure were attributable to an infiltrating malignancy.3 Cases of acute liver failure have previously been reported in AL amyloidosis.4-10 These cases usually presented due to myeloma, which was absent in our patient. He did not have any chronic inflammatory condition, malignancy, or family history of amyloidosis. The clinical presentation of progressive liver failure with rapid deterioration and subsequent death in our case is therefore remarkable and is now being recognized as a distinct presentation of primary amyloidosis.material. Hepatocytes showed pressure5,10
In contrast, if we examine cases of systemic AA amyloidosis, there is an associated amyloid deposition in other organs, which carries a poor prognosis. Lovat et al presented a series in which 138 patients had AA amyloidosis, 180 had AL amyloidosis, 99 had hereditary amyloid syndromes, and 67 had dialysis related (β2 microglobulin) amyloid.13 In that study, there was a significant drop in the 5-year survival from 72% in patients without liver involvement to 43% in patients with liver involvement.14 The diagnosis requires a liver biopsy and a bone marrow examination. We recommend the use of a transjugular technique to prevent a major bleed. Different histological patterns described in hepatic amyloidosis include a vascular pattern, in which primarily the hepatic arteries and arterioles are involved, and a sinusoidal/linear pattern, in which the amyloid deposits in the space of Disse along the hepatic sinusoids.15 These patterns of hepatic amyloid deposition occur singly or in conjunction and cannot be used to distinguish between the various forms of systemic amyloidosis.
Management of this condition remains unclear. Patients with myeloma and an indolent hepatic presentation are candidates for chemotherapy. The role of liver transplantation in the management of systemic amyloidosis is well established in the familial forms like familial amyloidotic polyneuropathy and transthyretin.16 On the other hand, there is only limited success with transplantation for treating AL amyloidosis as the disease progression is unaltered in the presence of a plasma cell dyscrasia. Therefore, the use of a combined approach with autologous stem cell transplant and liver transplant have been recently described.16,17
In conclusion, this case describes a patient with systemic AL amyloidosis, who presented with fatal liver failure, an unusual clinical presentation of primary hepatic amyloidosis. The diagnostic challenge in this case can serve as a differential in the etiological work-up for progressive liver failure. We urge clinicians to exercise a high degree of clinical suspicion to detect and refer such cases early. Aggressive chemotherapy and referral for transplant may improve outcomes in ACLF syndromes.
Author contributions: M. Premkumar and D. Rangegowda wrote the manuscript. R. Mahiwal and SK Sarin edited the manuscript. S. Grover provided the pathology images. SK Sarin is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained from the deceased patient’s next of kin for this case report.