Primary or light chain–associated (AL) amyloidosis is characterized by abnormal deposition of monoclonal immunoglobulin light chains in tissues and organs, with a wide range of clinical manifestations. Hepatic involvement in AL amyloidosis is seen in up to 90% of patients, with usually mild clinical manifestations, such as hepatomegaly and an elevated alkaline phosphatase level.1–3 Findings of portal hypertension, jaundice, and acute liver failure are rare, and in the majority of these cases, hepatomegaly was present.3–8 We present a unique case of systemic amyloidosis with acute liver failure, cholestatic jaundice, portal hypertension without hepatomegaly, and rapid progression to multiorgan failure.
A 48-year-old man from China with a history of hypertension, dyslipidemia, and type 2 diabetes mellitus, complicated with diabetic nephropathy, presented with a 1-month history of abdominal distension and bilateral pedal edema. He reported an episode of nonbloody diarrhea on a trip to Mexico requiring a short course of ciprofloxacin, but his symptoms had begun before this diarrheal illness. Physical examination revealed jaundice, ascites, and bilateral pitting pedal edema, without hepatosplenomegaly and other stigmata of chronic liver disease.
Initial investigations revealed cholestatic transaminitis with alkaline phosphatase (ALP) 1441 IU/L, gamma glutamic transferase (GGT) 1572 IU/L, bilirubin 41 μmol/L, alanine aminotransferase (ALT) 209 U/L, aspartate aminotransferase (AST) 272 U/L, and albumin 24 g/L. He had mild acute kidney injury with serum creatinine at 133 μmol/L. Otherwise, complete blood count, electrolytes, and international normalized ratio (INR) were normal. Viral serologies for acute hepatitis A to E, Epstein-Barr virus, cytomegalovirus, and HIV were negative. The patient was immune to hepatitis A, but not hepatitis B. Malaria, schistosomiasis, and strongyloides were ruled out. Antinuclear antibody, antimitochondrial antibody, anti–smooth muscle antibody, anti-liver-kidney microsomal antibody, alpha-1 antitrypsin, quantitative immunoglobulins, anti–neutrophil cytoplasmic antibody, angiotensin-converting enzyme level, and hemochromatosis genetic testing were negative. Peritoneal fluid analysis showed serum ascites albumin gradient of 1.9 g/dL consistent with portal hypertensive ascites. Ascitic fluid total protein was 8 g/L, and fluid albumin was less than 5 g/L. Despite high peritoneal fluid total protein, cardiac ascites was ruled out with cardiac echocardiogram showing no diastolic or systolic cardiac dysfunction. Peritoneal fluid culture and cytology were negative.
Abdominal computed tomography revealed ascites and esophageal varices but no cirrhosis or hepatomegaly (Figure 1). Doppler abdominal ultrasound showed no evidence of portal or hepatic vein thrombosis. Magnetic resonance cholangiopancreatography demonstrated no biliary pathology. Although initially the cause for his noncirrhotic portal hypertension and jaundice was unclear, his liver enzyme trended down to AST 151 U/L, ALT 133 U/L, GGT 1035 IU/L, ALP 835 IU/L, total bilirubin 44 μmol/L, and INR 1.1, and his creatinine remained stable at 131 μmol/L. His ascites improved with paracentesis and gentle diuresis; therefore, he was discharged home with outpatient gastroenterology follow-up.
Two months later, he was readmitted with deteriorating liver and renal function with nephrotic-range proteinuria (4.33 g/d). Blood work showed bilirubin 277 μmol/L, ALP 974 IU/L, GGT 932 IU/L, INR 1.5, albumin 11 g/L, and creatinine 288 μmol/L. Common etiologies for fulminant liver failure were ruled out again. Transjugular liver biopsy showed hepatic amyloidosis with extensive amorphous deposits within sinusoidal space (Figure 2). Because of procedural technical issues, hepatic venous pressure gradient and wedge pressure could not be measured. Congo red stain confirmed the presence of perisinusoidal and perivascular amyloid deposition with characteristic apple-green birefringence under the polarizer (Figure 3). Serum and urine protein electrophoresis with immunofixations were normal, but he had elevated serum-free kappa light chains at 2010 mg/L and free lambda light chains at 64.9 mg/L, in keeping with a free light chain monoclonal gammopathy. Bone marrow biopsy revealed plasma cell neoplasm with plasmacytosis of 30%–40% and amyloid deposition consistent with multiple myeloma. Upper endoscopy was performed for reported dysphagia and variceal surveillance, noted on imaging. Multiple yellow esophageal aphthous ulcerations were noted (Figure 4). Biopsies of the ulcers revealed amyloid depositions (Figure 5).
A screening echocardiogram demonstrated evidence of new diastolic dysfunction, hyperdynamic ejection fraction of 75%, and elevated brain natriuretic peptide (17,739 ng/L). He subsequently had a cardiac magnetic resonance imaging, demonstrating reversal of the nulling pattern, suggestive of a diffuse cardiac amyloid infiltration. Ultimately, the patient was diagnosed with systemic AL amyloidosis associated with multiple myeloma with liver, gastrointestinal tract, heart, and presumably renal involvement. Given systemic amyloidosis, he was not a candidate for liver transplant. He was then started on cyclophosphamide-bortezomib-dexamethasone chemotherapy, but his hepatic and renal dysfunction further deteriorated with worsening ascites and dialysis-dependent renal failure, not well tolerated due to persistent hypotension. He had multiple episodes of agitation and delirium but no overt hepatic encephalopathy. He was then transferred to the palliative care unit for supportive management and subsequently died of multiorgan failure, 3 months after his initial presentation.
Loudin et al demonstrated hepatic involvement in up to 95% of AL amyloidosis postmortem.9 Hepatomegaly, seen in 57 to 83% of patients, and elevated ALP are the most common findings.3,10 Cholestatic jaundice and portal hypertension are less frequent.3,9 Acute liver failure secondary to hepatic amyloidosis is quite rare and is usually accompanied by massive hepatomegaly.5–8,11–14 Hepatomegaly with infiltrative diseases serves as a clue to diagnosis. We hereby present a unique case of AL amyloidosis with significant hepatic dysfunction and rapidly progressive disease without hepatomegaly. The patient also had multiple esophageal ulcerations with amyloid deposits, which is rarely documented.15 This case may suggest that the degree of liver functional abnormality does not always correlate with the extent of hepatic amyloid infiltration.16 Although the prognosis of systemic amyloidosis remains poor, earlier diagnosis may improve survival, with sequential liver and stem cell transplantation and systemic chemotherapy.3,14,17
Author contributions: HJ Kim wrote the manuscript. W. Xiong provided the pathology images. M. Tomaszewski, EC Lam, and S. Moosavi edited the manuscript. S. Moosavi is the article guarantor.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
1. Iwata T, Hoshii Y, Kawano H, et al. Hepatic amyloidosis in Japan: Histological and morphometric analysis based on amyloid proteins. Hum Pathol. 1995;26(10):1148–53.
2. Desport E, Bridoux F, Sirac C, et al. Al amyloidosis. Orphanet J Rare Dis. 2012;7:54.
3. Ebert EC, Nagar M. Gastrointestinal manifestations of amyloidosis. Am J Gastroenterol. 2008;103(3):776–87.
4. Levy M, Fryd CH, Eliakim M. Intrahepatic obstructive jaundice due to amyloidosis of the liver. A case report and review of the literature. Gastroenterology. 1971;61(2):234–8.
5. Premkumar M, Rangegowda D, Vyas T, et al. Primary hepatic amyloidosis presenting as acute-on-chronic liver failure: ACG Case Rep J. 2017;4(1):e22.
6. Ales NC, Daniels JT, Frizell ER, Koff JM, Kaplan KJ, Wortmann GW. Multiple myeloma-associated amyloidosis manifesting as fulminant hepatic failure. South Med J. 2001;94(10):1036–8.
7. Cardoso BA, Leal R, Sá H, Campos M. Acute liver failure due to primary amyloidosis in a nephrotic syndrome: A swiftly progressive course. BMJ Case Rep. 2016;2016:bcr2016214392.
8. Ford M, Disney B, Shinde V, Ishaq S. Hepatic amyloidosis: A cause of rapidly progressive jaundice. BMJ Case Rep. 2018;2018:bcr2017222942.
9. Loudin M, Childers R, Zivony A, Lanciault C, Chang M, Ahn J. Liver failure secondary to amyloid light-chain amyloidosis. Am J Med. 2016;129(4):e19-e20.
10. Syed U, Ching Companioni RA, Alkhawam H, Walfish A. Amyloidosis of the gastrointestinal tract and the liver: Clinical context, diagnosis and management. Eur J Gastroenterol Hepatol. 2016;28(10):1109–21.
11. Park MA, Mueller PS, Kyle RA, Larson DR, Plevak MF, Gertz MA. Primary (AL) hepatic amyloidosis: Clinical features and natural history in 98 patients. Medicine (Baltimore). 2003;82(5):291–8.
12. Yamamoto T, Maeda N, Kawasaki H. Hepatic failure in a case of multiple myeloma-associated amyloidosis (k-AL). J Gastroenterol. 1995;30(3):393–7.
13. Casiraghi MA, De Paoli A, Assi A, et al. Hepatic amyloidosis with light chain deposition disease. A rare association. Dig Liver Dis. 2000;32(9):795–8.
14. Elnegouly M, Specht K, Zoller H, Matevossian E, Bassermann F, Umgelter A. Liver transplantation followed by autologous stem cell transplantation for acute liver failure caused by AL amyloidosis. Case report and review of the literature. Ann Hepatol. 2016;15(4):592–7.
15. Heitzman EJ, Heitzman GC, Elliott CF. Primary esophageal amyloidosis: Report of a case with bleeding, perforation, and survival following resection. Arch Intern Med. 1962;109(5):595–600.
16. Levine RA. Amyloid disease of the liver. Correlation of clinical, functional and morphologic features in forty-seven patients. Am J Med. 1962;33:349–57.
17. Rajkumar SV, Gertz MA. Advances in the treatment of amyloidosis. N Engl J Med. 2007;356(23):2413–5.