Amyloidosis: a convoluted story

Abstract

Amyloid is a substance that appears homogeneous and amorphous under the light microscope and stains pink with haematoxylin-eosin and metachromatically with methyl violet or crystal violet. Amyloid stained with Congo red produces an apple-green birefringence under polarized light. The amorphous hyaline-like appearance of amyloid is misleading because it is a fibrous protein. On electron microscopy, amyloid consists of rigid, linear, non-branching, aggregated fibrils that are 7·5–10·0 nm in width and of indefinite length. The fibrils are insoluble and generally resist proteolytic digestion. All types of amyloid appear the same with Congo red staining and with electron microscopy. However, the fibrils in primary amyloidosis (AL) consist of the variable portion of a monoclonal light chain (κ or λ); secondary amyloidosis (AA) fibrils consist of protein A, a non-immunoglobulin; familial amyloidosis fibrils are usually composed of mutated transthyretin (prealbumin); senile systemic amyloid fibrils consist of normal transthyretin; and amyloid associated with long-term dialysis consists of β2-microglobulin. In 1639, Nicolaus Fontanus (Fonteyn; Nicolao Fontano) (Fig 1) reported the autopsy of a young man with ascites, jaundice and epistaxis who had an abscess in the liver and a large spleen filled with white stones. This may have been the first description of the sago spleen of amyloidosis. Thomas Bartholin, discoverer of the lymphatic system in humans, described it in his Historiarum Anatomicarum Rariorum(Fig 2). He reported the autopsy of a woman whose spleen was so hard that it could scarcely be cut with a knife. Incision of the spleen produced a sound like that of the cutting of spongy timbers. Both of these autopsy reports were included among the 3000 collected in Theophili Boneti's Sepulchretum sive Anatomia Practica published in 1679 (Boneti, 1928) (Fig 3). Boneti was born in Geneva in 1620 and received his medical degree from the University of Bologna in 1643. He retired from practice in 1675 because of deafness, and devoted the rest of his life to the collection of medical knowledge. His Sepulchretum, containing 1700 pages, began with a dedication, lengthy preface and an impressive list of authors that began with Hippocrates and extended to the then current time. He divided the cases on the basis of anatomy such as the abdomen, thorax and head. However, he made few comments or deductions and came to no specific conclusions. The book also contains several pages of courteous encomiums from prominent 17th century physicians such as Bartholin and Johann Peyer. Many of his cases represented pulmonary tuberculosis with good clinical histories and convincing post-mortem studies. Forty pages were devoted to neoplasms, and their emphasis was on tumours of bones. He often attributed ascites to diseases of the spleen rather than the liver. Although the Sepulchretum is a great collection of cases in the history of pathology, it is marred by the lack of judgement in grouping and separating lesions and the uncritical acceptance of the cited author's opinion. Title page of Responsionum & Curationum Medicinalium, Nicolao Fontano. Historiarum Anatomicarum Rariorum, Thomae Bartholini. Sepulchretum sive Anatomia Practica, Theophili Boneti. Wainewright (1722) described a patient who had had ‘strumous swellings in his neck’ for several years, hepatomegaly (two to three times normal size), and ‘a clay-coloured pituitous substance’ in the liver, which some believe represented amyloid. F.V. Raspail (1794–1878) froze tissues for microscopic investigation. He also used alcohol to make the tissues more firm and the iodine test to demonstrate starch. Some consider Raspail the founder of histochemistry. J.J. Colin and H.F. Gaultier de Claubry reported in 1814 that starch appeared blue if tested with iodine. Schleiden in 1838 referred to the iodine test for starch. Apparently, Raspail introduced cellular pathology when he stressed the origin of new cells by division. It is not known whether Virchow knew the work of Raspail, the third edition of whose book was published in 1840 just before Virchow's career began (Schwartz, 1970). Abercrombie in 1828 described the liver as a uniform dull yellow that closely resembled the colour of impure beeswax. Antoine Portal was probably the first to describe substances similar to lard in the liver of an elderly woman in 1789. Portal subsequently described the liver of an 8-year-old boy with scrofula as very large and noted that when exposed to heat it hardened like albumin. He thought that the child had an albuminous obstruction. Lardaceous changes were reported in a letter by Merat in 1818 (Schwartz, 1970). Carl Rokitansky (1842) stated that patients with tuberculosis or syphilis had liver enlargement as a result of infiltration by a grey albuminous, gelatinous substance. He described the firm greyish material as ‘lardaceous-gelatinous.’ He stated that the lardaceous infiltration occurred in cases of scrofula (tuberculosis), syphilis and mercury poisoning. He thought that the lardaceous or ‘waxy’ livers were a type of fatty liver. George Budd (1808–1882; Fig 4) described a patient with an enormous liver that appeared pale. In another case, the liver was analysed and consisted of animal matter with increased albumin (16%) and only 5·75% fat. He concluded that the infiltrating substance was albuminous and not fatty. He also noted that the kidneys of two of his patients showed the same infiltration as in the liver (Budd, 1852). Budd noted that all four of his cases were associated with tuberculosis involving bone. George Budd 1808−1882. (From Doyle, 1988. By permission of The Royal Society of Medicine.) Gairdner (1854), in his report of the analysis of waxy degeneration of the liver by Dr James Drummond, found that the fat content was not increased above normal. In fact, he stated that the ‘waxy organ is unusually poor in oil.’ He had compared the fat content of the liver with waxy degeneration with the fat content in cirrhosis, fatty degeneration and normal people. In addition, there was a marked increase in the percentage of solids in the waxy liver. Gairdner concluded that the waxy liver represented a true degeneration in which there was a ‘metamorphosis of its glandular structure into a much more dense “albuminous material” than in the normal condition.’ He believed that this resulted in a reduction in function and loss of the typical structural characteristics of the liver. The term ‘amyloid’ was coined in 1838 by Matthias Schleiden, a German botanist, to describe a normal amylaceous constituent of plants. Rudolph Virchow, in 1854, used the term amyloid because of the peculiar reaction of the corpora amylacea of the nervous system with iodine. He was convinced that cerebral corpora amylacea could be considered identical to starch (Virchow, 1971). He preferred amyloid to the commonly used terms ‘lardaceous’ or ‘waxy’ changes. The French school preferred the term ‘lardaceous’ because the tissue looked like bacon, whereas the Edinburgh school preferred the term ‘waxy.’ They also used the term sagomilz (sago spleen) because its follicles were converted into the waxy changes. They thought that amyloid was more closely aligned with cellulose than starch. Virchow disagreed with Kekule and Schmidt who, like Budd, reported a high proportion of nitrogen in organs infiltrated by amyloid. Virchow thought that analysis of the whole liver was inadequate and stated that ‘only when we have discovered the means of isolating the amyloid substance, shall we be able to come to any definite conclusion with regard to its nature.’ Virchow believed that the pale organs infiltrated by amyloid resulted from ischaemia from the obstruction of vessels preventing the flow of blood. He pointed out that marasmus was a prominent feature of advanced amyloid disease. He described cases in which the entire digestive tract was involved. Virchow also noted that the iodine test showed reactivity with the glomeruli and the afferent arteries of the kidney. Johann Meckel noted that the sodium and iodine sulphuric-acid test produced a red or violet colour in many organs considered to be affected by lardaceous degeneration. He emphasized that the lardaceous changes were present not only in the liver and kidneys but also in the aorta, arteries and intestinal wall, which is the distribution of amyloid that is now recognized. Meckel had succeeded Virchow as prosector of the Charite Hospital in Berlin. He believed that the lardaceous deposits consisted of cholesterine. Meckel, who died at age 35, in his post-humous monograph, published by his friend T. Billroth, stated that lardaceous and waxy infiltration was not the result of cellulose degeneration, and that it had no resemblance to starch granules. Schwartz compared Virchow with Columbus, who headed for India and found America, whereas Virchow searched for starch in the human body and discovered amyloid (Schwartz, 1970). In 1859, Carl Friedreich and August Kekule reported that the waxy spleen contained no material that corresponded chemically to amylon or cellulose. Even though it consisted of albumoid compounds, they believed that the name ‘amyloid’ could not be changed. Primary amyloidosis was probably reported in 1856 when Samuel Wilks (Fig 5) described a 52-year-old man with lardaceous viscera in whom the changes were unrelated to syphilis, osteomyelitis, other osseous disease or tuberculosis. The patient had dropsy and albuminuria. At autopsy, the heart was hypertrophied and the spleen was hard and lardaceous. The kidneys were whitish and showed considerable lardaceous changes. However, the patient was atypical in that he had had episodes of dropsy for 8 years and this is much longer than the usual survival of patients with primary amyloidosis and nephrotic syndrome (Wilks, 1856). In 1865, Wilks published an additional 60 cases of lardaceous disease and noted that five of his 96 cases did not have evidence of an underlying disease such as syphilis, tuberculosis or bony disease. He disagreed with the use of the term ‘amyloid degeneration’ and emphasized its albuminoid nature. He took particular issue with the term ‘degeneration’ because the liver was filled with adventitious matter and was heavier than normal and, thus, the process was not degenerative. He stated that lardaceous involvement led to destruction of the healthy elements of the liver and kidney. He also mentioned that the term ‘waxy cast’ had been applied to the wax-like microscopic cast of the uriniferous tubules long before the term ‘waxy kidney’ came into use. He emphasized that waxy cast and waxy kidney were unrelated (Wilks, 1865). Wilks also reported involvement of the suprarenal (adrenal) glands with lardaceous disease in 1860. The patient had had syphilis and lardaceous disease involving the liver, kidneys and spleen. There was no mention of symptoms related to adrenal insufficiency, except that the patient had general cachexia. The adrenal glands were ‘large and remarkably firm’ (Wilks, 1860). Samuel Wilks 1824–1911. (From Doyle, 1988. By permission of The Royal Society of Medicine.) A committee of which Wilks was a member was appointed by the Royal Society of London to report ‘on the nature of the so-called Lardaceous Disease and as to the name by which it should be recognized.’ The committee believed that the tissue contained an increase of cholesterine and was nitrogenous, containing 13–14% nitrogen and, thus, of albuminous origin. However, the committee recommended that the term ‘lardaceous’ could be adopted by the Society because it was widely used and well understood (Report of the Committee on Lardaceous Diseases, 1871). Dickinson (1869) presented a case of lardaceous disease of the kidney attributed to an ovarian abscess. He postulated the lardaceous material ‘as a precipitation from the blood of fibrine which has been disassociated from the albumin and alkali with which it is normally connected.’ It is not clear why the term amyloidosis prevailed, but the reason was perhaps related to Virchow's standing as a pathologist and to the common use of the iodine stain as a diagnostic test (Doyle, 1988). The first case of amyloidosis associated with multiple myeloma was reported by Weber (1867). The autopsy revealed spontaneous fractures of the sternum with replacement by a greyish red substance containing many small nucleated cells. Identical findings were present in other bones. The left ventricle of the heart was hypertrophied, and the kidneys and spleen contained amyloid. Adams (1872) described a 60-year-old woman with lardaceous changes in the liver and spleen and multiple pathological fractures. The bone marrow was infiltrated with plasma cells and a pinkish gelatinous material. Despite these reports, many have attributed the first case of primary amyloidosis to Wild (1886). The patient, a 56-year-old woman, had ‘weakness of the heart muscle’ and died of erysipelas. At autopsy, the ventricles were firm and resistant and contained a hyaline material that stained with iodine, and methyl violet. and were also involved. The liver, spleen and kidneys were not by amyloid. There was no mention of the bone marrow the stains for amyloid. In of of and Rudolph of reported the use of in the of amyloid. The term was introduced by and used the term to describe the staining reaction of amyloid in All that the methyl were much than the iodine introduced methyl which to the nature of amyloid It is that Virchow the stains for amyloid as long as years their The stains were by Congo which was introduced by Congo red is an that is used for staining It stains all types of amyloid. The origin of the term is not A was in in to a several the Congo in This with the of the new the Congo was on the of and represented an to it is not that the was the name Congo red was used to stain tissue in but it was not that Congo red was found to to amyloid noted that an of Congo red in patients with amyloid resulted in of the from the plasma and its in amyloid He thought that this could be used for diagnostic because the stains and iodine had He found that revealed marked staining of the amyloid with Congo but staining of was the amyloid and the normal tissue it was to the amyloid. discovered that of the Congo tissue to in alcohol resulted in staining of only the amyloid. He recommended that stained with Congo then exposed to and with alcohol by stain resulted in staining only amyloid. He noted that hyaline tissue and corpora amylacea of the did not the Congo red He thought that Congo red a amyloid and than the use of methyl violet. and at the University of first described the birefringence when an amyloid from the of patients with disease apple-green birefringence when stained with Congo red and under polarized light. & first that all types of amyloid a structure when under the electron Although type of amyloid consists of a its deposits similar and structural Amyloid fibrils of amyloid A, and consist of five or In transthyretin amyloid contains four All amyloid fibrils have an The structure of amyloid consists of of the the The of and the of and the of the protein In to the amyloid amyloid and are also of amyloid Amyloid is a that is present in all types of amyloidosis. It amyloid fibrils from proteolytic but its function is amyloid deposits may be and a or of other pathological or amyloid may be and the of protein as the substance’ of amyloidosis. years he cases of multiple myeloma in which amyloid was present in the myeloma or the bone marrow and in which amyloid was present in other He emphasized the of amyloid in and He postulated that the myeloma cells produced amyloid but it could not be from the the amyloid with myeloma cells the bone and the and fatty He also noted that amyloid occurred with large or small of protein. He thought that by did not amyloidosis. He postulated that increased and of protein was & the of amyloid in plasma cells and believed that this was evidence of the of origin of amyloid. that amyloid be able to be as a substance, and that its to other then be also stated that amyloid in the tissues was to the of protein by the He emphasized the of amyloid in the and tissue in multiple myeloma in to its in liver, spleen and kidneys in secondary amyloidosis. He also thought there was a the amyloid associated with and the associated with protein. The of primary amyloidosis with multiple myeloma or a plasma was reported by & that protein an in primary amyloidosis. & reported that of amyloid fibrils a They this as a structure by the amyloid chain in a on so that chain were in an The of the chain to the of the produced and protein of amyloid fibrils from two and the of the The of a was identical except for of the first of amyloid protein and two of the first in the This that these two amyloid fibrils were of a It was then that monoclonal light could amyloid three and two from myeloma patients amyloidosis into their variable and the were exposed to with the two stained with Congo red and had a birefringence with microscopy. revealed fibrils in width and in length. revealed a typical of amyloid that amyloid fibrils could be from protein. The of analysis and that the fibrils were from the variable portion of the of the patients whose protein amyloid fibrils were known to have other or in to these are for the of amyloid fibrils in the of amyloid in the kidneys of when with monoclonal light from two patients with amyloidosis. The amyloid deposits were Congo with birefringence and had a They consisted of human monoclonal light and amyloid The of amyloid was by with protein had no or only amyloid The of is with and in longer and survival compared with is in patients and described a 52-year-old man who had had and of his for He had a loss of and and then and a had died of a similar At autopsy, microscopic revealed of a homogeneous substance in the The origin of these appeared to be a of the of and they were revealed a staining of the whereas no staining occurred with the and The blood vessels in were The authors postulated that the represented an of described diseases or a The appears in that the findings are with familial amyloidosis. In a woman from de who had a that was known as in the years he described patients from multiple who presented with an of by or and loss of The disease began in the or third of In addition, or loss of and and and occurred from or a of the revealed amyloid. In of a man who had for The patient was to because of were but a was found to have with and this led to a of amyloidosis. The first cases from and were reported in & published the findings of 60 patients with amyloidosis and from The patients were similar to from except the age at was years and and were more in the of and in have been reported with familial amyloid The disease usually and years of but the may in The amyloid fibrils of the and patients all consisted of transthyretin In reported that is for at in the transthyretin has been introduced as a for familial It is of to the same in and The may have been by from who in the The in is in the of de and on the of and this is with this than patients with familial have been in the could have in and then been to by who for the of and There is an of a a from a he be a of the introduced the of a new and into in the and may have been for of the presented at the on and This is of and is but it is not by analysis that multiple occurred at A with amyloidosis who were of origin and in was reported in The first is syndrome by involving the involvement is not and involvement not It is by a of transthyretin 1988). amyloid was reported in five of in a with amyloid heart in the or of It led to in years The amyloid in the heart consisted of transthyretin with a in 1988). from the of the was reported with amyloid from an of transthyretin the patients also had and This has been a than of transthyretin have been reported It is that many more be reported because of cerebral with amyloidosis has been in and the In the amyloid of a is found in the small and This has been & In the of familial cerebral amyloid cerebral and senile The amyloid is composed of identical to that found in disease except for a of at has been reported in and is by and systemic amyloidosis This of systemic amyloidosis is by a in the familial amyloidosis was reported by in present with and that to The amyloid deposits have been to have in and may involving the and It in the of and often as a result of The fibrils consist of a with a of for at 1988). additional have been reported with of have been reported The of the amyloidosis was & and similar have been found to the of transthyretin amyloid use of a other specific transthyretin have been the familial amyloidosis (AA) has been for reported the of an that to of the amyloid fibrils from a patient with familial They also three other from patients with secondary amyloidosis and reported identical This protein did not any known It subsequently was protein The amyloid fibrils of consist of protein A, a protein that is a of normal type of amyloidosis in familial which is by of and in the abdomen, or It was usually as and amyloidosis was not It is found in and than of patients have more than affected nephrotic syndrome and in the patient (AA) amyloidosis often in the of is in preventing of and and the of amyloidosis The familial is have been is also common in and amyloid deposits have been found in the heart in of patients years also have senile amyloidosis patients usually present with heart but the survival is years compared with in patients with heart by primary amyloidosis & The amyloid deposits consist of normal In patients long-term and and in the Amyloid in the and bone is for the The amyloid associated with dialysis consists of to Dr for the German This work was in by from the of