Primary systemic amyloidosis is an uncommon disease characterized by the extracellular deposition of insoluble fibrils derived from immunoglobulin light chains. Widespread deposition of amyloid fibrils causes multisystem organ dysfunction 15. The source of the light chains is a population of monoclonal plasma cells. A monoclonal protein can be found in the serum or urine (or both) of approximately 90% of patients with primary amyloidosis.
The heart, kidney, and peripheral nerves are most commonly affected by primary systemic amyloidosis. The liver is also a common site of amyloid deposition. In 1 autopsy series 1, 70% of the patients with primary systemic amyloidosis had liver involvement. However, deposition of amyloid in the liver rarely causes clinical manifestations 14,24,31. Nevertheless, patients with primary systemic amyloidosis who have biopsy-proven liver involvement (primary hepatic amyloidosis) have poor prognoses; 1 study 14 found the median survival of these patients to be 9 months, with a 5-year survival rate of 13% and a 10-year survival rate of 1%. We report the clinical features and natural history of primary systemic amyloidosis in 98 patients who had biopsy-proven liver involvement.
A computerized search was done of the medical records of all patients with primary systemic amyloidosis and biopsy-proven liver involvement who were evaluated at Mayo Clinic in Rochester, MN, from January 1, 1975, to December 31, 1997. This time frame was chosen to allow for a minimum of 5 years of follow-up that was free of censored observations in order to determine more accurately the natural history of the disease. Patients were excluded if they had secondary, familial, localized, or senile amyloidosis. Because of the objective of this study, patients with primary systemic amyloidosis were excluded if liver involvement was found only at autopsy. The study group comprised the 98 patients who satisfied these criteria. Permission to perform a retrospective review of the medical records was granted by the Mayo Foundation Institutional Review Board in compliance with federal regulations.
Continuous data were reported as means (± standard deviations) and discrete data were reported as numbers of patients (and percentages). The main analysis end point was survival. Overall survival was estimated with the method of Kaplan and Meier 22. Analyses of the effects of potential risk factors on survival were performed with log-rank tests 38 for risk factors composed of discrete variables and Cox proportional hazards models 7 for continuous data. Risk factors for survival were evaluated univariately as well as multivariately. The multivariate analysis consisted of stepwise variable selection. The resulting model was validated using a bootstrap resampling technique 43. All statistical tests were 2-sided, and the threshold of significance was set at α = 0.05. Computerized analyses used SAS version 6.12 (SAS Institute Inc., Cary, NC) and S-Plus (Insightful Corp., Seattle, WA) with a Sun Ultra II computer (Sun Microsystems Inc., Palo Alto, CA).
Of the 98 patients, 68 (69%) were men and 30 (31%) were women. The median age of the study group was 58.5 years (women, 58 yr; men, 58.5 yr). Involuntary weight loss was the most common symptom, experienced by 71 patients (72%). The average weight loss for these patients was 10.4 kg. Notably, these patients who had involuntary weight loss waited an average of 6.7 months after the onset of weight loss before seeking medical attention. Other symptoms experienced were fatigue in 59 patients (60%), abdominal pain in 52 (53%), edema in 25 (26%), anorexia in 25 (26%), early satiety in 19 (19%), nausea in 15 (15%), and dysgeusia in 10 (10%).
The most common physical examination finding was hepatomegaly, found in 79 patients (81%). The median extent of liver enlargement for these patients was 8 cm below the right costal margin. Other physical examination findings were ascites in 41 patients (42%), purpura in 14 (15%), splenomegaly in 10 (10%), and spider angiomata in 7 (7%). Only 1 patient had an enlarged tongue.
The median concentration of serum creatinine was 100 μmol/L. In fact, only 11 of 94 patients (12%) had a concentration of serum creatinine of 180 μmol/L or more. However, of the 92 patients who had urinalyses done, 82 (89%) had proteinuria; the median 24-hour urine protein was 1.4 g. Total cholesterol results were available for 74 patients. Of these, 59 (80%) had a concentration of total cholesterol greater than 5.20 mmol/L (200 mg/dL). Notably, only 27 patients (46%) with hypercholesterolemia had nephrotic syndrome at the time of liver biopsy.
The concentration of alkaline phosphatase was the most frequently abnormal blood test result: 81 of the 94 patients (86%) had abnormal results, and 57 (61%) had values of 500 U/L or more (that is, twice the upper limit of the reference range) (Table 1). Of these 57 patients, 49 (86%) had hepatomegaly, whereas 8 (14%) did not. The concentration of aspartate aminotransferase was more than twice the upper limit of the reference range (that is, ≥62 U/L) in 35 of 95 patients (37%). Of these 35 patients, 28 (80%) had hepatomegaly, whereas 7 (20%) did not. The concentration of total bilirubin was greater than 34 μmol/L in 20 of 95 patients (21%). Of these 20 patients, 15 (75%) had hepatomegaly, whereas 5 (25%) did not.
Anemia was uncommon. In fact, in 89 of 97 patients (92%), the concentration of hemoglobin was more than 100 g/L (mean, 134 ± 22 g/L; median, 136 g/L). Of the 76 patients for whom peripheral blood smears were available, 21 (28%) had Howell–Jolly bodies (see Table 1). Serum protein electrophoresis detected a monoclonal protein in only 36 of 96 patients (38%). Among those who had a monoclonal protein by serum protein electrophoresis, only 2 (6%) had a monoclonal spike of at least 3 g/dL. The median size of the monoclonal spike was 0.8 g/dL. Serum protein electrophoresis showed hypogammaglobulinemia in 27 patients (28%). Serum immunoelectrophoresis or immunofixation detected a monoclonal protein in 43 of 96 patients (45%). Among these 43 patients, IgG λ was revealed in 13, free λ in 8, IgA λ in 5, IgA κ in 5, free κ in 4, IgM λ in 4, and other immunoglobulins in 4. Urine protein immunoelectrophoresis with immunofixation detected a monoclonal protein in 62 of 93 patients (67%). Of these 62 patients, 56 (90%) had a monoclonal spike of 1 g/24 h or less. Urine immunoelectrophoresis or immunofixation revealed λ chains in 36 patients and κ chains in 26 patients. The median urine monoclonal spike was 0.14 g. Overall, 76 of 92 patients (83%) had either a serum or urine monoclonal protein.
Liver tissue was obtained from all patients. The most common indications for liver biopsy were unexplained hepatomegaly (64 patients; 65%), unexplained elevated results of liver tests (27; 28%), and unexplained elevated concentrations of alkaline phosphatase (21; 21%). (The sum is greater than 100% because several patients had more than 1 indication for liver biopsy.) Differential diagnosis data were available for 54 patients. Of these, clinicians considered amyloidosis in the differential before liver biopsy for only 14 patients (26%). The most common diagnosis included in the differential diagnosis was malignancy (primary and metastatic disease), occurring in 31 patients (57%). Hepatitis was included in the differential diagnosis for 8 patients (15%), lymphoma for 8 (15%), and gallbladder disease for 5 (9%).
Liver tissue was obtained by transcutaneous needle biopsy in 58 patients (59%), laparotomy in 23 (23%), transjugular hepatic biopsy in 3 (3%), peritoneoscopy in 2 (2%), and unspecified methods in 12 (12%). Four patients (4%) bled after the liver biopsy, 2 of whom required blood transfusions. However, no biopsy-associated deaths or hepatic ruptures occurred.
The pattern of amyloid deposition in the liver was given in the pathology reports of 77 patients. For 51 patients (66%), deposition was solely sinusoidal; for 10 (13%), solely vascular; and for 16 (21%), both sinusoidal and vascular. In addition to liver biopsy, many patients underwent biopsy of other tissues. Fat aspirate was positive for amyloid in 43 of 54 patients (80%). Bone marrow biopsy was positive for amyloid in 69 of 84 patients (82%). Rectal biopsy was positive for amyloid in 13 of 20 patients (65%). Many patients had extrahepatic manifestations of amyloidosis (Table 2).
The overall median survival for the 98 patients was 8.5 months. The 5-year survival was 16.9%, and the 10-year survival was 6.6%. Patients with a platelet count greater than 500 × 109/L (twice the upper limit of the reference range) had a median survival of 5.4 months, compared with 8.5 months for patients with platelet counts of 500 × 109/L or less (p = 0.045) (Figure 1). The median survival among patients with a concentration of alkaline phosphatase of 500 U/L or more was 5.4 months, compared with 18.7 months among patients with a concentration less than 500 U/L (p = 0.004). Patients with a prothrombin time of 13 seconds or more had a median survival of 3.7 months, compared with 9.2 months for patients with a prothrombin time in the reference range (p = 0.018). Patients with a β2-microglobulin level greater than 230 nmol/L had a median survival of 2.8 months, compared with 52.2 months among patients with a level of β2-microglobulin in the reference range (p = 0.046). Patients who had congestive heart failure before liver biopsy had a median survival of 0.5 month, compared with 11.2 months among patients with no prior history of congestive heart failure (p = 0.001) (Figure 2). The median survival of patients with a concentration of serum bilirubin greater than 34 μmol/L was 1 month, compared with 15.6 months among patients with a concentration of bilirubin in the reference range (p < 0.001) (Figure 3).
Multivariate analysis showed that shortened survival was predicted by the presence of congestive heart failure before liver biopsy, concentrations of total bilirubin greater than 34 μmol/L, and a platelet count greater than 500 × 109/L (Table 3). After the confirmation of primary hepatic amyloidosis on liver biopsy, patients with congestive heart failure before liver biopsy were 4.4 times more likely to die than patients without congestive heart failure. Patients with a platelet count greater than 500 × 109/L were 2.4 times more likely to die than those with platelet counts of 500 × 109/L or less. Finally, patients with a serum level of bilirubin greater than 34 μmol/L were 12.5 times more likely to die than those with a bilirubin level less than or equal to 34 μmol/L.
We describe the clinical features and natural history of primary systemic amyloidosis in 98 patients with biopsy-proven liver involvement (primary hepatic amyloidosis). Similar to the male-female ratio of patients with primary amyloidosis involving other sites, the male–female ratio of our patients was 2:1. In addition, the clinical history did not provide specific clues to the diagnosis of amyloid involvement of the liver, and most of our patients presented with nonspecific symptoms, such as involuntary weight loss, fatigue, abdominal pain, edema, and anorexia. For example, the average weight loss was 10.4 kg. However, a similar degree of weight loss has been reported among patients with primary systemic amyloidosis without liver involvement 26.
Although not a specific clue to the diagnosis of primary hepatic amyloidosis, hepatomegaly occurred in most of our patients (79; 81%). Indeed, previous studies have reported that 24%–34% of patients with primary systemic amyloidosis present with hepatomegaly 25,29 and that 80%–90% of patients with primary amyloidosis with liver involvement have hepatomegaly 15.
However, not all patients with primary systemic amyloidosis and hepatomegaly have hepatic amyloidosis 14. In an autopsy study of patients with primary systemic amyloidosis, 3 of 9 patients (33%) with hepatomegaly had passive congestion of the liver without hepatic amyloidosis 32. In another autopsy study, 20% of 45 patients with primary systemic amyloidosis and palpable hepatomegaly had no sign of hepatic amyloidosis 30.
It has been suggested that stigmata of chronic liver disease (for example, spider angiomas and palmar erythema) are rare findings in primary hepatic amyloidosis 42. Indeed, only 7 of our patients (7%) had spider angiomas and 2 (2%) had palmar erythema or Dupuytren contracture, or both. However, 41 (42%) had ascites sometime during their illness, a higher frequency than reported previously (20%) 20.
Routine laboratory tests may provide clues to the diagnosis of primary hepatic amyloidosis. One study found that 88% of patients with hepatic amyloidosis had proteinuria 14. Similarly, 89% of our patients had proteinuria. It has been reported 45 that abnormalities of liver test results are minimal and occur late in hepatic amyloidosis. One group reported 39 that these abnormalities correlate poorly with the extent of hepatic amyloidosis. Frequently, the concentration of alkaline phosphatase is elevated in hepatic amyloidosis; often the elevation is greater than expected from clinical findings 15,30. Among our patients, 81 of 94 (86%) had an elevated concentration of alkaline phosphatase. Furthermore, in 35 of 95 of our patients (37%), the concentration of aspartate aminotransferase was greater than twice the upper limit of the reference range, and 20 of 95 (21%) had a concentration of total bilirubin greater than 34 μmol/L. In our patients, hepatomegaly was associated with a greater likelihood of abnormal results for liver tests.
Congestive heart failure was present in 10 of our patients (10%) at the time of diagnosis. Patients with congestive heart failure may have abnormal liver test results 8,9,40. However, these abnormalities are generally mild and are not associated with clinical liver disease 23. In a previous study 23, patients with passive hepatic congestion due to severe congestive heart failure had minimal elevations of aspartate aminotransferase and alkaline phosphatase. The authors concluded that concentrations of alkaline phosphatase 2 or more times greater than the upper limit of the reference range or a concentration of bilirubin greater than 39 μmol/L suggests liver or biliary disease. Indeed, our study showed marked elevations of alkaline phosphatase but minimal elevations of aspartate aminotransferase. Hence, one should consider conditions other than passive hepatic congestion (such as hepatic amyloidosis) in patients with congestive heart failure and markedly elevated alkaline phosphatase.
Other authors 6 have speculated that new-onset hypercholesterolemia may be an early manifestation of primary hepatic amyloidosis. At the time of liver biopsy, most of our patients (80%) had hypercholesterolemia, and of these, nearly one-half had nephrotic syndrome. Our data neither support nor disprove that new-onset hypercholesterolemia is an early manifestation of primary hepatic amyloidosis. However, our data do suggest that clinicians should consider secondary causes of hypercholesterolemia (for example, nephrotic syndrome) in patients with hypercholesterolemia and, furthermore, that clinicians should consider the diagnosis of amyloidosis in patients with nephrotic syndrome.
In amyloidosis, hyposplenism results from massive deposits of amyloid in the spleen, interfering with splenic phagocytic function and resulting in the formation of Howell–Jolly bodies 14. Peripheral blood smears were available for 76 patients, and 21 (28%) had Howell–Jolly bodies, suggesting hyposplenism. In addition, in the spleen up to 30% of platelets can be sequestered and, with loss of splenic phagocytic function, thrombocytosis can occur 14. Furthermore, 16 of our patients (16%) had platelet counts greater than 500 × 109/L. Hence, hyposplenism in a patient with liver disease may suggest the diagnosis of systemic amyloidosis.
Patients with primary hepatic amyloidosis may have a prolonged thrombin time. However, this prolongation does not correlate with an increased risk of abnormal bleeding 2,13,15,36,47. Notably, we did not determine the prevalence of a prolonged thrombin time among our patients.
It has been suggested that prolongation of the prothrombin time in hepatic amyloidosis is unusual 39. However, a recent study 36 found that 82 of 337 patients (24%) with primary systemic amyloidosis had a prolonged prothrombin time. In multivariate analysis, a prolonged prothrombin time was the only coagulation abnormality associated with abnormal bleeding at sites other than the skin. Notably, the authors of that study did not report coagulation findings specific for patients with primary hepatic amyloidosis 36. However, we found that 32 of 91 of our patients with primary hepatic amyloidosis (35%) had a prolonged prothrombin time. These results suggest that clinicians should monitor the prothrombin time of their patients who have primary hepatic amyloidosis, and if prothrombin time is prolonged, these patients should be closely observed for abnormal bleeding.
For most of our patients (58%), transcutaneous liver biopsy was used to establish the diagnosis of hepatic amyloidosis. No deaths associated with liver biopsy occurred among our patients. Although hemorrhage is the most important complication of a liver biopsy, only 4 of our patients (4%) experienced hemorrhage related to liver biopsy, consistent with results in previous reports 11,12,14,17,21,48. Of these patients, however, 2 (2%) required blood transfusions, a rate higher than the overall reported risk (0.1%–0.2%) of liver biopsy-associated bleeding requiring blood transfusions 14,48.
Notably, of the 4 patients in our study who bled after liver biopsy, 3 had a prolonged prothrombin time. However, 29 of 32 of our patients (91%) who had a prolonged prothrombin time underwent uneventful liver biopsy without bleeding, suggesting that a prolonged prothrombin time is not a reliable predictor of bleeding complications related to this procedure in patients with hepatic amyloidosis. Nevertheless, because a prolonged prothrombin time is the only coagulation abnormality associated with abnormal bleeding in primary hepatic amyloidosis 36, clinicians should be cautious when obtaining a liver biopsy specimen from patients suspected of having hepatic amyloidosis and should monitor them closely for postbiopsy bleeding.
Some studies have suggested that amyloid is largely confined to the portal blood vessels in primary hepatic amyloidosis 30,44. However, others suggest that amyloid can be found in a sinusoidal and vascular distribution 1,3,33, a distribution found in 21% of our patients. The clinical significance of these pathologic findings is unknown.
Because liver biopsy is not free of risks, clinicians may consider subcutaneous fat aspirate or bone marrow biopsy (or both) for patients suspected of having hepatic amyloidosis. A previous study 15 reported that 18 of 19 patients (95%) with primary hepatic amyloidosis had subcutaneous fat aspirate or bone marrow biopsies that were positive for amyloid. In our study, subcutaneous fat aspirate biopsy was positive for amyloid in 43 of 54 patients (80%), and bone marrow biopsy was positive in 69 of 84 patients (82%).
Clinicians considered amyloid in the initial differential diagnoses for only 14 of 54 patients (26%). Malignancy was the most common disease included in the differential diagnoses; 28 patients (32%) were thought to have primary hepatic cancer or metastatic disease before the liver biopsy was done. However, because most of our patients presented with nonspecific symptoms and physical examination findings, it is not surprising that amyloid was not considered in the initial differential diagnoses for most of our patients. Nevertheless, hepatic amyloidosis should be considered when patients have unexplained hepatomegaly and elevated results for liver tests 14. Aside from performing liver, bone marrow, or subcutaneous fat biopsy, one should also perform immunofixation to exclude the diagnosis of amyloidosis. Indeed, 76 of 92 of our patients (83%) had a monoclonal protein in serum or urine or both.
The median survival of patients with primary hepatic amyloidosis has been reported as 9 months 14. Similarly, the overall median survival of our patients was 8.5 months. Several articles suggest that patients with hepatic amyloidosis have poor prognoses if they have jaundice 10,35,37,41 or an elevated concentration of bilirubin 18,19,34,49), which is consistent with our findings: median survival was only 1 month among our patients with a concentration of bilirubin greater than 34 μmol/L. In addition, multivariate analysis showed that 2 other factors were predictive of a poor prognosis: the presence of congestive heart failure before liver biopsy and a platelet count greater than 500 × 109/L.
Early recognition of patients with primary amyloidosis is crucial to the initiation of therapy. Among patients with primary systemic amyloidosis, treatment with melphalan, prednisone, or colchicine, or combinations of these drugs, improves survival 28,46. In fact, in a recent trial, patients with primary systemic amyloidosis were randomly assigned to receive colchicine alone, melphalan and prednisone, or melphalan, prednisone, and colchicine 27. Survival was greatest among patients who were assigned to a regimen containing melphalan. Even though conventional therapies improve the survival of patients with primary systemic amyloidosis, long-term survival is uncommon 28. High-dose chemotherapy followed by rescue with peripheral stem cell therapy may result in higher survival rates than those achievable with conventional therapy 4,5,16.
Because primary hepatic amyloidosis is a rare cause of hepatomegaly and abnormal results from liver tests, clinicians may not consider amyloidosis as a cause of these findings. However, several clinical clues may prompt clinicians to recognize primary systemic amyloidosis with liver involvement. These clues include involuntary weight loss, unexplained hepatomegaly, elevated concentrations of alkaline phosphatase and other liver test abnormalities, proteinuria, evidence for hyposplenism (for example, Howell–Jolly bodies on peripheral blood smear), and monoclonal protein in serum or urine or both. These clues, especially if the patient has a history of congestive heart failure or nephrotic syndrome, suggest primary systemic amyloidosis with liver involvement. Although patients with primary hepatic amyloidosis have a poor prognosis, its accurate recognition may have important therapeutic implications, because some patients may benefit from treatment, including systemic chemotherapy.
1. Buck FS, Koss MN. Hepatic amyloidosis: Morphologic differences between systemic AL and AA types. Hum Pathol. 22: 904–7, 1991.
2. Butler WM, Baldwin PE. Prolongation of thrombin and reptilase times in patients with amyloidosis and acquired factor X deficiency. South Med J. 77: 648–51, 1984.
3. Chopra S, Rubinow A, Koff RS, Cohen AS. Hepatic amyloidosis: A histopathologic analysis of primary (AL) and secondary (AA) forms. Am J Pathol. 115: 186–93, 1984.
4. Comenzo RL, Vosburgh E, Falk RH, Sanchorawala V, Reisinger J, Dubrey S, Dember LM, Berk JL, Akpek G, LaValley M, O’Hara C, Arkin CF, Wright DG, Skinner M. Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: Survival and responses in 25 patients. Blood. 91: 3662–70, 1998.
5. Comenzo RL, Vosburgh E, Simms RW, Bergethon P, Sarnaci D, Finn K, Dubrey S, Faller DV, Wright DG, Falk RH, Skinner M. Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: One-year follow-up in five patients. Blood. 88: 2801–6, 1996.
6. Couture P, LeBlanc F, Gagnon P, Gagnon O, Gagne C. Hyperlipidemia as the first biochemical manifestation of primary hepatic amyloidosis. Am J Gastroenterol. 92: 1046–7, 1997.
7. Cox DR. Regression models and life-tables (with discussion). J R Stat Soc [B]. 34: 187–220, 1972.
8. Dunn GD, Hayes P, Breen KJ, Schenker S. The liver in congestive heart failure: A review. Am J Med Sci. 265: 174–89, 1973.
9. Felder L, Mund A, Parker JG. Liver function tests in chronic congestive heart failure. Circulation. 2: 286–97, 1950.
10. Finkelstein SD, Fornasier VL, Pruzanski W. Intrahepatic cholestasis with predominant pericentral deposition in systemic amyloidosis. Hum Pathol. 12: 470–2, 1981.
11. Froehlich F, Lamy O, Fried M, Gonvers JJ. Practice and complications of liver biopsy: Results of a nationwide survey in Switzerland. Dig Dis Sci. 38: 1480–4, 1993.
12. Garcia-Tsao G, Boyer JL. Outpatient liver biopsy: How safe is it? [Editorial.] Ann Intern Med. 118: 150–3, 1993.
13. Gastineau DA, Gertz MA, Daniels TM, Kyle RA, Bowie EJ. Inhibitor of the thrombin time in systemic amyloidosis: A common coagulation abnormality. Blood. 77: 2637–40, 1991.
14. Gertz MA, Kyle RA. Hepatic amyloidosis (primary [AL], immunoglobulin light chain): The natural history in 80 patients. Am J Med. 85: 73–80, 1988.
15. Gertz MA, Kyle RA. Hepatic amyloidosis: Clinical appraisal in 77 patients. Hepatology. 25: 118–21, 1997.
16. Gertz MA, Lacy MQ, Dispenzieri A, Gastineau DA, Chen MG, Ansell SM, Inwards DJ, Micallef IN, Tefferi A, Litzow MR. Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med. 113: 549–55, 2002.
17. Gilmore IT, Burroughs A, Murray-Lyon IM, Williams R, Jenkins D, Hopkins A. Indications, methods, and outcomes of percutaneous liver biopsy in England and Wales: An audit by the British Society of Gastroenterology and the Royal College of Physicians of London. Gut. 36: 437–41, 1995.
18. Goenka MK, Bhasin DK, Vasisth RK, Dhawan S. Hepatic amyloidosis presenting with severe intrahepatic cholestasis. J Clin Gastroenterol. 23: 134–6, 1996.
19. Hoffman MS, Stein BE, Davidian MM, Rosenthal WS. Hepatic amyloidosis presenting as severe intrahepatic cholestasis: A case report and review of the literature. Am J Gastroenterol. 83: 783–5, 1988.
20. Isselbacher KJ, Podolsky DK. Infiltrative and metabolic diseases affecting the liver. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s principles of internal medicine 14th ed vol 2. New York: McGraw-Hill, pp 1717–1720, 1998.
21. Janes CH, Lindor KD. Outcome of patients hospitalized for complications after outpatient liver biopsy. Ann Intern Med. 118: 96–8, 1993.
22. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 53: 457–81, 1958.
23. Kubo SH, Walter BA, John DH, Clark M, Cody RJ. Liver function abnormalities in chronic heart failure: Influence of systemic hemodynamics. Arch Intern Med. 147: 1227–30, 1987.
24. Kyle RA. Amyloidosis. In: Wiernik PH, Canellos GP, Kyle RA, Schiffer CA, eds. Neoplastic diseases of the blood. vol 2. New York: Churchill Livingstone, pp 607–651, 1985.
25. Kyle RA, Gertz MA. Primary systemic amyloidosis: Clinical and laboratory features in 474 cases. Semin Hematol. 32: 45–59, 1995.
26. Kyle RA, Gertz MA. Amyloidosis of the liver. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s diseases of the liver, 8th ed vol 2. Philadelphia: Lippincott-Raven, pp 1199–204, 1999.
27. Kyle RA, Gertz MA, Greipp PR, Witzig TE, Lust JA, Lacy MQ, Therneau TM. A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med. 336: 1202–7, 1997.
28. Kyle RA, Greipp PR. Primary systemic amyloidosis: Comparison of melphalan and prednisone versus placebo. Blood. 52: 818–27, 1978.
29. Kyle RA, Greipp PR. Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin Proc. 58: 665–83, 1983.
30. Levine RA. Amyloid disease of the liver: Correlation of clinical, functional and morphologic features in forty-seven patients. Am J Med. 33: 349–57, 1962.
31. Levy M, Fryd CH, Eliakim M. Intrahepatic obstructive jaundice due to amyloidosis of the liver: A case report and review of the literature. Gastroenterology. 61: 234–8, 1971.
32. Levy M, Polliack A, Lender M, Eliakim M. The liver in amyloidosis. Digestion. 10: 40–51, 1974.
33. Looi LM, Sumithran E. Morphologic differences in the pattern of liver infiltration between systemic AL and AA amyloidosis. Hum Pathol. 19: 732–5, 1988.
34. Melato M, Manconi R, Magris D, Morassi P, Benussi DG, Tiribelli C. Different morphologic aspects and clinical features in massive hepatic amyloidosis. Digestion. 29: 138–45, 1984.
35. Mir-Madjlessi SH, Farmer RG, Hawk WA Jr. Cholestatic jaundice associated with primary amyloidosis. Cleve Clin Q. 39: 167–75, 1972.
36. Mumford AD, O’Donnell J, Gillmore JD, Manning RA, Hawkins PN, Laffan M. Bleeding symptoms and coagulation abnormalities in 337 patients with AL-amyloidosis. Br J Haematol. 110: 454–60, 2000.
37. Peters RA, Koukoulis G, Gimson A, Portmann B, Westaby D, Williams R. Primary amyloidosis and severe intrahepatic cholestatic jaundice. Gut. 35: 1322–5, 1994.
38. Peto R, Peto J. Asymptotically efficient rank invariant procedures (with discussion). J R Stat Soc [A]. 135: 185–207, 1972.
39. Podolsky DK. Infiltrative, genetic, and metabolic diseases affecting the liver. In: Braunwald E, Fauci AS, Isselbacher KS, Kasper DL, Hauser SL, Longo DL, Jameson JL, eds. Harrison’s principles of internal medicine 15th ed vol 2. New York: McGraw-Hill, pp 1766–70, 2001.
40. Richman SM, Delman AJ, Grob D. Alterations in indices of liver function in congestive heart failure with particular reference to serum enzymes. Am J Med. 30: 211–25, 1961.
41. Rubinow A, Koff RS, Cohen AS. Severe intrahepatic cholestasis in primary amyloidosis: A report of four cases and a review of the literature. Am J Med. 64: 937–46, 1978.
42. Rubio PA, Farrell EM, Lehane DE. Primary liver amyloidosis producing obstructive jaundice. South Med J. 72: 891–2, 1979.
43. Sauerbrei W, Schumacher M. A bootstrap resampling procedure for model building: Application to the Cox regression model. Stat Med. 11: 2093–109, 1992.
44. Sherlock S. Diseases of the liver and biliary system, 4th ed. Philadelphia: FA Davis, pp 507–512, 1968.
45. Sipe JD, Cohen AS. Amyloidosis. In: Fauci AS, Braunwald E, Isselbacher KJ, Wilson JD, Martin JB, Kasper DL, Hauser SL, Longo DL, eds. Harrison’s principles of internal medicine 14th ed vol 2. New York: McGraw-Hill, pp 1856–1860, 1998.
46. Skinner M, Anderson J, Simms R, Falk R, Wang M, Libbey C, Jones LA, Cohen AS. Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med. 100: 290–8, 1996.
47. Yood RA, Skinner M, Rubinow A, Talarico L, Cohen AS. Bleeding manifestations in 100 patients with amyloidosis. JAMA. 249: 1322–4, 1983.
48. Zamcheck N, Klausenstock O. Liver biopsy (concluded). II. The risk of needle biopsy. N Engl J Med. 249: 1062–9, 1953.
49. Zeijen RN, Sels JP, Flendrig JA, Arends JW. Portal hypertension and intrahepatic cholestasis in hepatic amyloidosis. Neth J Med. 38: 257–61, 1991.