Hepatic amyloidosis: morphologic differences between systemic AL and AA types

The liver is almost universally involved in systemic amyloidosis. Patterns of topographic distribution of amyloid within the liver lobule have been recognized, but the reliability of using these for classification of amyloid type is in question. We examined 286 livers from cases of systemic amyloidosis obtained from autopsies at Los Angeles County-University of Southern California Medical Center, classifying them as AL or AA type by means of the potassium permanganate Congo red-staining method along with a specific anti-AA antiserum. Prior publications have asserted that deposition of secondary (AA) amyloidosis is limited to the vessels in the portal tract, constituting a "vascular" pattern, and that in primary (AL) amyloidosis the deposits exhibit a "sinusoidal" pattern in that they are seen along hepatic sinusoids as well as in portal vessels. We confirmed that AL amyloid involves the portal vessels as frequently as AA amyloid and that deposition occurred significantly more frequently in the portal stroma, the central vein, and the "sinusoidal" areas. However, we also found a "sinusoidal" pattern in 29 of 78 cases of secondary (AA) amyloidosis; in 14 of these, more than half of the sinusoidal spaces were replaced by amyloid deposits. We also noted that in 23 of the 29 AA amyloidosis cases with "sinusoidal" involvement, a "sago" pattern of distribution of amyloid in the spleen was present. No consistent association of a specific chronic inflammatory disease with "sago" spleen and "sinusoidal" deposits could be documented. We conclude that topographic distribution of amyloid within the liver lobule is not a reliable method of distinguishing AA from AL amyloidosis and that specific staining methods must be used if the physician is to be able to attempt modern therapeutic modalities.     

Primary cardiac amyloidosis with 20-year survival

BACKGROUND: The natural history of primary amyloidosis is poor, and for patients with symptomatic cardiac involvement, survival is generally less than 6 months. Even among treated patients with amyloid heart disease, survival beyond 5 years is rare. CASE REPORT: We report a patient with primary cardiac amyloidosis who is currently alive 20 years after his initial diagnosis. The extent and subtype of amyloid were documented by endomyocardial biopsy both at the time of initial diagnosis and 20 years later. To our knowledge, this is the longest survival ever reported for a patient with cardiac involvement by primary amyloidosis. CONCLUSION: The remarkably long stabilization of amyloid deposition in this patient may be attributed to early diagnosis, early institution of therapy, and, possibly, favorable genetic factors.     

Morphologic differences in the pattern of liver infiltration between systemic AL and AA amyloidosis

Biopsy and necropsy tissue from 31 unselected patients with systemic amyloidosis, in which there was histologic evidence of liver involvement, were reviewed with reference to the location and pattern of amyloid deposition in the liver. Amyloidosis was classified into AA and AL types on the basis of immunohistochemistry and permanganate reaction of the amyloid deposits. Nineteen were categorized as AA (secondary) and 12 as AL (primary) amyloidosis. Deposition of AA amyloid was limited to the walls of vessels in the portal tract, constituting a "vascular" pattern. In AL amyloidosis, the deposits exhibited a "sinusoidal" pattern in that they were seen along hepatic sinusoids as well as in vessel walls. This difference was statistically significant (P less than .001). The histologic pattern of liver infiltration offers a valuable clue in the classification of systemic amyloidosis and provides information that may be useful in the selection of patients for therapy.     

Sarcoidosis and immunoglobulin lambda II light-chain amyloidosis diagnosed after orthotopic heart transplantation: a case report and review of the literature.

Cardiac involvement by sarcoidosis and concomitant deposition of AL amyloid is an uncommon association. We describe the case of a 53-year-old African-American man with a 7-year history of dilated nonischemic cardiomyopathy and severe cardiac failure who underwent orthotopic heart transplantation. His prior cardiac biopsies had only mild myocyte hypertrophy and minimal interstitial fibrosis. After surgery, numerous sarcoid granulomas and amyloid deposition were identified in the native heart. Six days after the transplant the patient died due to aspiration bronchopneumonia and acute renal failure. At autopsy, both sarcoidosis and immunoglobulin (Ig) lambda light-chain amyloidosis were present in the native atria, lungs, thyroid, liver, spleen, and kidneys. Sarcoid granulomas alone were present in the parathyroids, lymph nodes, and bone marrow. Amyloid deposition alone was present in the aorta, stomach, large bowel, and urinary bladder. There was no evidence of plasma cell dyscrasia, or underlying gammopathy. This unusual association was described in only two other cases in the medical literature. However, this is the first case of sarcoidosis and AL amyloidosis with successful sequencing and identification of Ig lambda light-chain amyloid, and in which there was no evidence of plasma cell dyscrasia.     

The pattern of amyloid deposition in the lung

A review of routine histopathological samples and autopsies examined at the Department of Pathology, University of Malaya revealed 15 cases of amyloidosis of the lung. Two were localized depositions limited to the lung while in the remainder, lung involvement was part of the picture of systemic amyloidosis. Both cases of localized amyloidosis presented with symptomatic lung/bronchial masses and a clinical diagnosis of tumour. Histology revealed "amyloidomas" associated with heavy plasma cell and lymphocytic infiltration and the presence of multinucleated giant cells. In both cases, the amyloid deposits were immunopositive for lambda light chains and negative for kappa chains and AA protein. One was a known systemic lupus erythematosus patient with polyclonal hypergammaglobulinaemia. The other patient was found to have plasma cell dyscrasia with monoclonal IgG lambda gammopathy. Both patients did not develop systemic amyloidosis. In contrast, lung involvement in systemic AA amyloidosis was not obvious clinically or macroscopically but was histologically evident in 75% of cases subjected to autopsy. Amyloid was detected mainly in the walls of arterioles and small vessels, and along the alveolar septa. It was less frequently detected in the pleura, along the basement membrane of the bronchial epithelium and around bronchial glands. In one case of systemic AL amyloidosis associated with multiple myeloma, an "amyloidoma" occurred in the subpleural region reminiscent of localized amyloidosis. These cases pose questions on (1) whether localized "tumour-like" amyloidosis is a forme fruste of systemic AL amyloidosis and (2) the differing pattern of tissue deposition of different chemical types of amyloid fibrils, with the suggestion that light chain amyloid has a greater tendency to nodular deposition than AA amyloid.     

Orthotopic liver transplantation for familial amyloidotic polyneuropathy: a pathological study

Familial amyloidotic polyneuropathy (FAP), a hereditary form of systemic amyloidosis with clinically significant neuropathy and cardiomyopathy, is caused by a genetic defect of the transthyretin gene, which is mostly synthesized in the liver. Orthotopic liver transplantation (OLT) is thought to eliminate the amyloidogenic protein and currently is the only definitive treatment for this disorder. The aim of this study was to define the distribution and extent of amyloid deposition in tissues from these patients and evaluate the suitability of the resected FAP livers for transplantation into non-FAP patients. Surgical specimens from 14 patients removed at the time of OLT and autopsy tissues from 3 of the 14 were examined histologically using hematoxylin and eosin and Congo red-stained sections. The extent of amyloid deposits was evaluated, semiquantitatively graded from negative to marked, and correlated with clinical course and patient outcome. Amyloid deposits were consistently seen in hilar and vagus nerves. Liver lobular involvement was minimal in 1 and absent in the other 13 cases, with portal arterial amyloid deposits seen in 7 cases. At autopsy, extensive amyloid deposition in the heart was seen in all 3 cases with involvement of the conduction system. The extent of amyloid deposition at OLT did not correlate with the duration of symptoms before OLT or patient outcome after OLT. In conclusion, liver parenchymal involvement in FAP is minimal, and these explants are suitable for grafting in non-FAP patients. The recipients of such grafts must be carefully observed for the development of any amyloid-related disease, particularly cardiomyopathy. Of the tissues removed at OLT, the histopathologic confirmation of FAP is most consistently made by the examination of hilar and vagus nerves.     

Systemic Amyloidosis Associated With Factor X Deficiency

An autopsy case of amyloidosis associated with factor X deficiency is reported. The patient showed a markedly decreased level of factor X (9% normal) and an extremely shortened half-life of intravenously infused factor X. Amyloid deposition was present in most of the visceral organs with special involvement of the liver and spleen. The amyloid in this case was thought to be AL protein, since it was potassium-permanganate-resistent and a small amount of Bence Jones protein was detected after dimethyl sulfoxide therapy. Electron microscopic study revealed a typical appearance of amyloid fibrils radiating from invaginated cell membrane of Kupffer cells, which may indicate rather rapid turnover of the amyloid. Rapidity and severity of amyloid deposition, especially in the liver and spleen, may play an important role in the development of the factor X deficiency associated with systemic amyloidosis. ACTA PATHOL. JPN. 34: 639–647, 1984.     

Clinicopathological importance of deposits of amyloid in the femoral head.

The pattern of amyloid deposits in the femoral head is described in four cases, two of which had deposits of amyloid related to age and two of which had generalised systemic amyloidosis (one of primary amyloidosis, one of multiple myeloma). The deposition of amyloid in the articular cartilage of the femoral head was similar in all four cases. Heavy deposits of synovial amyloid were identified in the case with primary amyloidosis and in one of the cases with amyloidosis related to age. Both cases of generalised systemic amyloidosis showed abundant deposits of amyloid in the bone marrow. Amyloid was not present in the bone marrow of either case with amyloidosis related to age. The importance of these findings is discussed in relation to the pathogenesis of the arthropathy syndrome of a rheumatoid type described in cases of primary amyloidosis and multiple myeloma.     

Histomorphological variations in systemic AA amyloidosis: clues of AA protein polymorphism

The histological location of amyloid within various organs in 25 cases of systemic AA amyloidosis was studied with a view to determine whether different morphological patterns exist in this category of amyloidosis. Although morphological variations due to progressive severity of disease were observed, there were appreciable variations in the patterns of amyloid deposition in the kidney and spleen that could not be simply explained on those grounds. Eleven (61%) of 18 kidneys examined showed severe glomerular involvement with mild degrees of vascular deposition while the remaining seven showed predominantly vascular involvement. The glomerular pattern appeared to be more ominous, being significantly associated with severe proteinuria or chronic renal failure. In nine (69%) of 13 spleens examined, amyloid was confined to the walls of small and medium-sized arteries while in the remaining four, vascular involvement was less severe and amyloid was deposited mainly along the reticulin of the white pulp. Possible explanations for these different patterns included resorption and redistribution of amyloid within the body during the course of the disease, and variation in tissue deposition as a manifestation of polymorphism of amyloid proteins. The latter appeared more feasible in view of the recent demonstration of SAA polymorphism and AA heterogeneity in man.     

Splenic amyloidosis: correlations between chemical types of amyloid protein and morphological features

Sixty-one autopsy cases of splenic amyloidosis were reviewed to assess the relationship between the morphological patterns and chemical types of amyloid protein. On the basis of immunohistochemical reactions of amyloid protein, the cases were classified into 34 cases of AA and 27 of AL amyloidosis. Amyloid deposition in the spleen was divided into three major sites: the red pulp, the white pulp, and blood vessels. Red pulp involvement by amyloid was noted in 52% of the AL cases but in none of the AA cases. White pulp amyloid deposition was found in 70% of the AL and 35% of the AA cases. This difference was statistically significant (P less than 0.001). On the other hand, vascular deposition of amyloid was invariably noted in all cases with AA or AL amyloidosis, affecting the AA cases rather severely. These results strongly suggest that the widely held concept of deposition of amyloid as predominantly vascular in AL amyloidosis and parenchymal in AA amyloidosis requires revision. Our findings indicate that parenchymal, especially the red pulp, involvement is a consistent feature of AL amyloidosis, whereas vascular involvement is a finding common to both types of systemic amyloidosis.     

Effects of sporadic transthyretin amyloidosis frequently on the gallbladder and the correlation between amyloid deposition in the gallbladder and heart: A forensic autopsy-based histopathological evaluation

The aim of the study is to evaluate the clinicopathological features of cholecystic ATTR deposition in patients with cardiac involvement, investigate the correlation of amyloid deposition severity in the gallbladder and the heart, and compare its prevalence in the gallbladder and other organs. Fifty patients with sporadic ATTR amyloidosis were identified. Of these, we evaluated 15 patients who underwent gallbladder sampling accurately. Among 10 patients (67%) with cholecystic deposition, six exhibited detectable deposition in the hematoxylin and eosin-stained specimens, and all of them displayed obstructive vascular deposition (VD). The severity of gall bladder VD was statistically correlated with that of cardiac VD and atrial interstitial deposition (ID). Additionally, all patients exhibiting cholecystic ID displayed severe ventricular and atrial IDs. In visceral organs excluding the heart, amyloid deposition was commonly observed in the lungs (93%), followed by the gastrointestinal tract (47%‒80%), liver (60%) and periosteal tissues (53%). The involvement of the gallbladder was prevalent and comparable to that of the gastrointestinal tract. Moreover, the severity of cholecystic deposition was correlated with that of cardiac deposition. Therefore, pathologists should be aware that sporadic ATTR amyloidosis is a common condition and should not be overlooked.     

Risikostratifizierung und Therapie kardialer Amyloidosen

Cardiac amyloidoses are a heterogeneous group of cardiomyopathies that are resistant to treatment and are associated with a poor outcome. Standard heart failure treatment is usually not well tolerated and the underlying disease remains unaffected. The clinical picture is uncharacteristic. Cardiac amyloidosis is often associated with dysfunction of additional organs. Early cardiac amyloid involvement usually reveals left ventricular hypertrophy, impairment of longitudinal shortening and diastolic ventricular function. Without adequate therapy (bi-)ventricular hypertrophy will progress to severe systolic ventricular function decrease. The combination of low voltage pattern, left ventricular hypertrophy and granular sparkling is characteristic for advanced cardiac amyloid involvement. Cardiac magnetic resonance imaging and scintigraphy yield further information on the pattern and severity of cardiac involvement. In unclear cases (left ventricular) endomyocardial biopsy is necessary. Detection of early cardiac involvement and proper identification of patients at high risk for sudden cardiac death due to rapid progressive amyloidosis is still incompletely defined. Referral to specialized centers is strongly recommended.     

Morphologic and chemical variation of the kidney lesions in amyloidosis secondary to rheumatoid arthritis

The kidneys of 20 patients who died of secondary systemic amyloidosis due to rheumatoid arthritis were studied histologically, and four of these were shown to have an uncommon pattern of deposition with almost no glomerular involvement but heavy deposits in the outer zone of the medulla. In three of the four patients frozen tissue was available. Immunochemical characterization of amyloid fibrils from these three cases showed that the major subunit amyloid fibril protein was protein AA, typical of secondary amyloidosis. Gel chromatography of fibrils revealed an uncommon elution pattern with two retarded major protein peaks. Both these proteins showed immunologic identity with protein AA and had N-terminal amino acid sequences identical with that protein but differed in size obviously due to a shortening of the C-terminal in one of the proteins. The reason for the correlation between the pattern of deposition of amyloid and alterations in protein AA is unclear but might be due to variations in enzymes responsible for the cleavage of the amyloid fibril subunit precursor protein SAA.     

Recurrent cardiac amyloidosis following previous heart transplantation

Recurrent cardiac amyloidosis has been reported in the literature. We present two cases, one at 41 months after heart transplant and autologous stem cell transplant, and the other, at 83 months following heart transplantation. The former is the first case ever reported of a patient with amyloid light chain amyloidosis with systemic recurrence following these two treatment modalities, and the latter is a patient with hereditary amyloidosis, whose interval to disease recurrence is the longest ever reported for this type.     

Hepatic amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms.

The liver is a major site of amyloid deposition. The spectrum of histopathologic changes in the liver was studied in 38 patients with systemic amyloidosis (25 with primary or myeloma-associated amyloidosis [AL] and 13 with secondary, reactive [AA] amyloidosis). Overall architectural distortion, alterations of portal triads, as well as predilection for topographic deposition in the parenchyma and/or blood vessel walls were noted. Significant histopathologic differences in AL or AA amyloid liver involvement included 1) portal fibrosis, seen in 7 of 25 (28%) AL patients and 8 of 13 (62%) AA patients (P = 0.05), 2) parenchymal amyloid deposition in 25 of 25 (100%) AL amyloid and 10 of 13 (77%) AA amyloid patients (P = 0.04), and 3) vascular amyloid deposition found in 17 of 25 (68%) with AL amyloid and 13 of 13 (100%) patients with AA amyloid (P = 0.02). These data vary from the widely held concept that deposition of amyloid is predominantly vascular in the AL form and parenchymal in amyloid AA. Clearly, however, in individual cases significant overlap occurred, and characterization of amyloid types based on morphologic distribution of amyloid deposits may be possible in only a minority of cases. In most cases, differentiation of amyloid AL and amyloid AA forms requires clinical, histochemical, immunochemical, and sometimes more elaborate laboratory amino acid sequence studies for accurate identification.     

Isolated cardiac amyloidosis associated with sudden death

An unusual case of localized cardiac amyloidosis was associated with sudden death in the absence of prior symptoms of heart disease. Autopsy studies showed amyloid deposition in the ventricular myocardium and conduction system; there were no deposits in other viscera, and evidence of a plasma cell dyscrasia was lacking. Thus, it appears that isolated involvement of the heart by amyloidosis may cause death, even in patients who do not have a history of congestive heart failure or arrhythmia.     

Systemic amyloidosis terminating in cardiac insufficiency

An autopsy case of systemic amyloidosis is presented. The patient, a 57-year-old male, died of congestive heart failure. Autopsy revealed systemic amyloidosis which involved the heart, liver, spleen, kidneys, lymph nodes, tongue, prostate, rectum, and small blood vessels of various organs. In the heart, amyloid deposited diffusely in the myocardium, subendocardial tissue, and blood vessel walls. A lot of vacuolated cardiac muscle fibers were noted. Electron microscopic examination of the myocardium revealed that amyloid fibrils surrounded most of the cardiac muscle fibers in the very close vicinity of their basement membranes. Fashion of the amyloid deposition throughout various organs and the mechanism of heart failure are discussed.     

Livers from patients with apolipoprotein A-I amyloidosis are not suitable as "domino" donors.

Orthotopic liver transplantation, by eliminating the major site of amyloidogenic protein synthesis, is currently the only definitive treatment of most hereditary amyloidoses. Because of the minimal parenchymal involvement, the explanted livers from familial amyloidotic polyneuropathy (FAP) patients have been transplanted into non-FAP patients in a "domino" fashion. The aim of this study was to evaluate the extent of amyloid deposits in explanted livers from two patients with apolipoprotein A-I amyloidosis, with the Arg26 mutation, to determine their suitability as domino donors. A detailed histologic review of the explanted livers from two patients was performed and assessed for the extent of amyloid deposition by routine and Congo red stains. Both patients had identical histopathologic features. The liver parenchymal involvement was strikingly severe. Large patches of amyloid separated hepatic cords, with accentuation around the central veins. All portal triads were consistently and markedly involved with amorphous eosinophilic deposits within the connective tissue compressing the bile ducts and vascular structures. Hilar vessels had patchy deposits. No involvement of hilar nerve branches was seen. The hepatic parenchyma is extensively involved in hereditary Apolipoprotein A-I amyloidosis, with the Arg26 mutation. These livers, removed at orthotopic liver transplantation, are not suitable for domino donation.     

Amyloid deposits in lymph nodes: A morphologic and immunohistochemical study

In a series of approximately 80,000 lymph nodes, amyloid deposition was found in 18; 12 of those nodes were selected, on the basis of availability of specimens, for investigation by immunohistochemical typing to identify the protein of origin and by correlation with morphologic criteria and clinical information. Four patterns of amyloid deposition were identified: lymph node vessel involvement, follicular deposition, diffuse deposition, and a combination of follicular and diffuse deposition. All cases were classified immunohistochemically with the amyloid type-specific antisera anti-AA, anti-A lambda, anti-A kappa, anti-ASc1, and anti-AF. Immunoglobulin-derived protein (AL) in lymph nodes was found in every case of isolated amyloidosis, lymphoplasmacytic/lymphoplasmacytoid immunocytoma, plasmacytoma, and idiopathic amyloidosis. Among the cases of AL amyloidosis were nine of A lambda and one of the A kappa type. AA protein was present in two cases of reactive systemic amyloidosis. There was no useful morphologic correlation with the immunohistochemically identified amyloid types.     

Cardiac amyloidosis. Therapeutic and diagnostic difficulties with reference to two different forms of the disease

Two male patients with primary cardiac amyloidosis are described. Patient 1 presented with typical effort angina pectoris with no ischemic electrocardiographic changes and a normal coronary angiogram. At necropsy, a severe diffuse, intravascular amyloid deposition was observed in the intramural coronary arteries. In patient 2 the presenting symptom was congestive heart failure with echocardiographic evidence of asymmetric septal hypertrophy and pericardial effusion. Technetium-99m pyrophosphate scintigraphy showed diffuse myocardial uptake, and the diagnosis of cardiac amyloidosis was confirmed in the postmortem examination. The diagnostic and therapeutic problems associated with cardiac amyloidosis are discussed in the light of these case reports.