Pituicytoma with Gelsolin Amyloid Deposition

Pituicytoma is a rare low-grade (WHO grade I) sellar region glioma. Among sellar tumors, pituitary adenomas, mainly prolactinomas, may show amyloid deposits. Gelsolin is a ubiquitous calcium-dependent protein that regulates actin filament dynamics. Two known gene point mutations result in gelsolin amyloid deposition, a characteristic feature of a rare type of familial amyloid polyneuropathy (FAP), the Finnish-type FAP, or hereditary gelsolin amyloidosis (HGA). HGA is an autosomal-dominant systemic amyloidosis, characterized by slowly progressive neurological deterioration with corneal lattice dystrophy, cranial neuropathy, and cutis laxa. A unique case of pituicytoma with marked gelsolin amyloid deposition in a 67-year-old Chinese woman is described. MRI revealed a 2.6-cm well-circumscribed, uniformly contrast-enhancing solid sellar mass with suprasellar extension. Histologically, the lesion was characterized by solid sheets and fascicles of spindle cells with slightly fibrillary cytoplasm and oval nuclei with pinpoint nucleoli. Surrounding brain parenchyma showed marked reactive piloid gliosis. Remarkably, conspicuous amyloid deposits were identified as pink homogeneous spherules on light microscopy that showed apple-green birefringence on Congo red with polarization. Mass spectrometric-based proteomic analysis identified the amyloid as gelsolin type. Immunohistochemically, diffuse reactivity to S100 protein and TTF1, focal reactivity for GFAP, and no reactivity to EMA, synaptophysin, and chromogranin were observed. HGA-related mutations were not identified in the tumor. No recurrence was noted 14 months after surgery. To the knowledge of the authors, amyloid deposition in pituicytoma or tumor-associated gelsolin amyloidosis has not been previously described. This novel finding expands the spectrum of sellar tumors that may be associated with amyloid deposition.     

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.     

Postmortem findings in primary familial amyloidosis with polyneuropathy.

The pathology of primary familia amyloidosis with polyneuropathy is described on the basis of post-mortem examination of six cases from Northern Sweden. Clinically the disease is characterized by progressive sensory and motor disturbances with loss of sensation, muscular wasting and flaccid paralysis. Impotence, urinary bladder dysfunction, motility disturbances of the gastro-intestinal tract and postural hypotension indicate affection of the autonomic nervous system as well. Malabsorption, cardiac insufficiency and vitreous opacites also occur. As regards the distribution of amyloid, the following findings seemed to be characteristic. Usually there were no gross lesions indicating the amyloid disease. Histopathologically, amyloid deposits were observed in great extent in the peripheral nervous system and in various parts of the peripheral autonomic nervous system as well. It occurred extensively in the walls of blood vessels of various calibres, in the perivascular collagenous connective tissue and adjacent to the smooth musculature. Amyloid deposition was also found more or less abundantly in various other organs and tissues. No deposits, however, or only insignificant amounts, were found in the central nervous system, either in the parenchyma of the liver, in the islets of Langerhans, or in the bone marrow. Clinical manifestations seemed to be related to the local deposition of the amyloid substance. Our clinical and pathological findings in this particular type of familial amyloidosis conformed mostly to those previously described.     

Relationship between glomerular mesangial cell proliferation and amyloid deposition as seen by ultrastructural and morphometric analysis in experimental kala-azar of the hamster

Light and electron microscopic studies combined with a morphometric analysis of the hamster glomerulus in experimental kala-azar showed progressive hyperplasia of mesangial cells beginning on the 10th day and reaching a peak on the 20th day after infection. Afterward, the number of mesangial cells declined and a progressive rise of amyloid deposits over the mesangial matrix was observed. This system for amyloid production is unique if we consider that probably one cell, the mesangial cell, is involved in glomerular amyloid deposition. Our data support a slight modification in the sequence of events of the biphasic theory of amyloid formation. We observed that the number of mesangial cells declines when amyloid deposition increases and that mesangial cell morphology in this stage is not that of an actively secreting cell. It is therefore hypothesized that amyloid precursor material is secreted into the matrix during the proliferative phase. In the second phase, amyloid deposits occur in the extracellular media close to functionally impaired mesangial cells.     

Impact of homozygosity for an amyloidogenic transthyretin mutation on phenotype and long term outcome

Although amyloidogenic transthyretin (ATTR) mutations are common in several populations, such as black Americans, the small number of diagnosed patients homozygous for TTR amyloid and the short follow up in most studies has until now prevented an analysis of their phenotype. In Sweden, nine homozygous patients from eight families carrying the ATTR mutation Val30Met, which gives rise to fatal neuropathic amyloidosis (FAP), have been identified and have now been followed for up to 15 years. This has enabled an analysis of the phenotype of homozygous patients. Genetic testing and detection of amyloid deposits in the vitreous body or in intestinal or skin biopsies confirmed the diagnosis in all patients. The patients'' symptoms were obtained from medical records. For comparison, we used a group of 35 heterozygous non-transplanted patients with FAP (18 men and 17 women), who had been evaluated at the Department of Medicine, Umeå University Hospital before their deaths. Vitreous amyloidosis was the most prevalent symptom in the homozygous group, and in two patients it was the only manifestation of the disease during their lifetime. The age at onset was not different from that of heterozygous patients, and their survival tended not to be shorter but actually longer than for heterozygotes. Homozygosity for the mutation associated with FAP, ATTR Val30Met, does not implicate a more severe phenotype for Swedish patients. The most common symptom was vitreous opacity, which may be the only manifestation of the disease. These findings point to the possibilities of different pathways for amyloid formation, or the presence of hitherto unknown genes operating in amyloid formation.     

A transthyretin variant (alanine 71) associated with familial amyloidotic polyneuropathy in a French family.

A transthyretin (TTR) mutation is described in a 44 year old French woman from Caen who presented at the age of 40 with neuropathy in all four extremities, diarrhoea, and orthostatic hypotension. Her father died with a similar syndrome including vitreous opacities. A nerve biopsy from the proband showed amyloid deposits which stained with anti-transthyretin. Direct genomic DNA sequencing of TTR exon 3 showed both thymine and cytosine in the position corresponding to the second base of codon 71. This codes for a variant alanine (GCG) as well as the normal valine (GTG), indicating that the proband is heterozygous for the substitution. Since this substitution does not result in the creation or abolition of a restriction endonuclease recognition site, a new technique (PCR-IMRA) was used to create an RFLP. Using a 24 bp nucleotide mutagenesis primer in the PCR reaction, a new NspBII site is created on amplification of the variant allele. With this method a 170 bp TTR exon 3 PCR product was generated for both the normal and the variant allele. On digestion of the PCR product with NspBII, DNA from a heterozygous subject showed both the 170 bp undigested product from the normal allele and a 146 bp digestion product from the variant allele. By PCR-IMRA, two of five children of the proband were positive for the variant allele. This non-radioactive technique gives a rapid method for testing subjects at risk for this mutation.     

Vitreous humour and cerebrospinal fluid hypoxanthine concentration as a marker of pre-mortem hypoxia in SIDS.

AIMS--To assess the rate at which premortem hypoxia occurs in sudden infant death syndrome (SIDS) when compared with death in early childhood. METHODS--The hypoxanthine concentration was measured as a marker of premortem hypoxia in vitreous humour and cerebrospinal fluid samples obtained at necropsy from 119 children whose ages ranged from 1 week to 2 years. RESULTS--Increasing interval between death and necropsy was accompanied by an increase in the hypoxanthine concentration of vitreous humour for the first 24 hours, at a rate of 8.3 mumol/l/hour. Thereafter, there was little change with time, and the results wer corrected to 24 hours according to a regression equation. Cerebrospinal fluid concentrations showed no significant change with time following death. Patients were divided into three groups according to the cause of death: SIDS, cardiac or pulmonary disease, and others. Median values for the cerebrospinal fluid hypoxanthine concentrations were not significantly different among the groups and no difference could be shown between the vitreous humour hypoxanthine concentration in cases of SIDS and those children dying from other causes. Patients with established cardiac or pulmonary disease had a significantly reduced vitreous humour hypoxanthine concentration which may have reflected the premortem use of artificial ventilation. CONCLUSIONS--The results of this study do not support the view that pre-mortem hypoxia is a common feature in SIDS when compared with other causes of death.     

FAMILIAL AMYLOID POLYNEUROPATHY WITH MARKED HYPERTROPHY OF THE PERIPHERAL NERVES

Autopsy findings in a 40-year-old male with heredofamilial amyloidosis and polyneuropathy are reported. He had been suffering from progressive autonomic as well as sensorimotor dysfunctions. Prominent amyloid deposit was found in the kidney, heart, thyroid, and testis, and less in the interstitium and small vessels of almost all organs. The peripheral nerves, some showing prominent hypertrophy, were most severely involved by amyloid deposit in a form of stellate mass, which ultrastructurally consisted of radially arranged amyloid filaments. In the hypertrophied nerves and ganglia, in addition to amyloid, massive accumulation of acid mucopolysaccharide (AMPS) was seen filling up the interstitial space, which was the cause of hypertrophy. Ultrastructurally, AMPS was seen as finely granular substance. An extracted amyloid from the kidney showed 8 nm filament on negative staining and was estimated of having a molecular weight of 14,000.     

Familial amyloid polyneuropathy with marked hypertrophy of the peripheral nerves

Autopsy findings in a 40-year-old male with heredofamilial amyloidosis and polyneuropathy are reported. He had been suffering from progressive autonomic as well as sensorimotor dysfunctions. Prominent amyloid deposit was found in the kidney, heart, thyroid, and testis, and less in the interstitium and small vessels of almost all organs. The peripheral nerves, some showing prominent hypertrophy, were most severely involved by amyloid deposit in a form of stellate mass, which ultrastructurally consisted of radially arranged amyloid filaments. In the hypertrophied nerves and ganglia, in addition to amyloid, massive accumulation of acid mucopolysaccharide (AMPS) was seen filling up the interstitial space, which was the cause of hypertrophy. Ultrastructurally, AMPS was seen as finely granular substance. An extracted amyloid from the kidney showed 8 nm filament on negative staining and was estimated of having a molecular weight of 14,000.     

Detection of choroid- and retina-antigen reactive CD8 and CD4 T lymphocytes in the vitreous fluid of patients with birdshot chorioretinopathy

Birdshot chorioretinopathy (BSCR), a progressive form of non-infectious uveitis, is the strongest HLA-associated disease described to date, with >95% of the patients displaying HLA-A29. Since indirect evidence indicates the involvement of T cells in the etiopathology of the disease, we now isolated, cultured and analyzed the vitreous fluid-infiltrating T cells from two BSCR patients with respect to their phenotype, cytokine profile, clonal distribution and antigen specificity. Phenotypic analyses revealed the predominant presence of both CD4⁺ and CD8⁺ T cells in vitreous fluid. Further analyses on short term expanded and cloned T cells suggested that eye-infiltrating T cells generally displayed a Th1 like cytokine profile with secretion of high levels of IFN-γ and TNF-α. In one patient an oligoclonal CD4⁺ and CD8⁺ T cell infiltration, with a moderate to strongly skewed TCR Vβ usage was suggestive for an antigen driven infiltration/expansion. Indeed, a number of intraocular CD4⁺ and CD8⁺ T cells responded to crude retinal and choroidal lysates. These results, which demonstrate for the first time the existence of eye-antigen-specific T cells in the vitreous fluid of BSCR patients, substantiate the current view on the role of eye-antigen specific T cells in the etiopathology of BSCR.     

The impact of aging in dementia: It is time to refocus attention on the main risk factor of dementia

Alzheimer’s disease (AD) represents the most common form of dementia among old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved, and no cure is available. The amyloid hypothesis has been recently questioned due to the failure of amyloid-centered treatments. The fact that cognitively normal old age subjects have substantial amyloid deposition in the brain comparable to the levels observed in AD patients suggests that amyloid accumulation may enter into the normal process of aging and what really triggers neuronal death and clinical manifestation is the loss of function due to an energetic failure. With this viewpoint article, we aim to challenge the traditional view of amyloid as the leading cause of AD. Conversely, we propose the core feature of aging, that is the progressive brain energy decline, as the main risk factor for dementia in older persons. Thus, a bioenergetic deficit secondary to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. The optimization of brain energetics should become a key component in future strategies for preventing and treating dementia.     

Avian amyloidosis.

Although amyloid deposits have been described for more than a century and a half, its proteinaceous and fibrillar nature was not revealed until after 1950. Biochemical characterization of amyloids has brought to light that several non-related proteins can re-organize into amyloid fibrils. In some domestic and caged wild birds, and especially waterfowl, amyloidosis is a well recognized pathological disorder and is an important cause of death in Anseriformes. Its regular occurrence in Galliformes has been recognized more recently, where amyloid deposits occur mainly in the joints in contrast to other species studied so far. Avian amyloidosis is systemic in nature, being classified by amino acid sequencing and, monoclonal and polyclonal antibodies as of the AA-type amyloid, also named reactive or secondary amyloid. The pathogenesis of both AA and other types of amyloidosis is a complex phenomenon that is not well understood. It has been shown that the occurrence of certain predisposing conditions and chronic infections, inflammations or tumours increase strongly the serum levels of the hepatic acute phase reactant serum amyloid A (SAA), the precursor protein of amyloid protein A (AA). Although an increased pool of precursor protein is necessary for amyloid to develop and while certain amino acid substitutions may favour amyloidogenicity giving rise to unstable intermediate protein conformations that easily re-organize into fibrils, the action of other factors which are discussed in this review, seems of vital importance at the initiation of fibrillogenesis. As the clinical symptoms of amyloidosis generally are non-specific, diagnosis requires histopathology following biopsy or necropsy. AA-amyloidosis is a fatal progressive disease in birds and other species. Currently no curative treatment is available, therefore special attention should be paid to prevention focusing on hygiene and avoidance of stress.     

Azoospermia due to testicular amyloidosis in a patient with familial Mediterranean fever

We describe a patient suffering from familial Mediterranean fever (FMF) who presented to our clinic with secondary infertility of 2 years due to amyloid A amyloidosis. His spermiogram disclosed azoospermia. A testicular biopsy revealed hyalinized tubules devoid of full spermatogenesis and containing abundant amyloid, confirmed by Congo red stain. We suggest that testicular amyloidosis be taken into consideration when dealing with azoospermic FMF patients. In view of the progressive nature of amyloid accumulation in the testis we propose to follow routinely the spermiogram of FMF patients with renal amyloidosis. Furthermore, consideration of sperm cryopreservation is suggested in these cases. In FMF patients with azoospermia consideration of testicular biopsy is recommended as early as possible in order to increase the chance of sperm retrieval.     

Antibody-mediated resolution of light chain-associated amyloid deposits

Primary light-chain-associated (AL) amyloidosis is characterized by the deposition in tissue of monoclonal light chains as fibrils. With rare exception, this process is seemingly irreversible and results in progressive organ dysfunction and eventually death. To determine whether immune factors can effect amyloid removal, we developed an experimental model in which mice were injected with amyloid proteins extracted from the spleens or livers of patients with AL amyloidosis. Notably, the resultant amyloidomas were rapidly resolved, as compared to controls, when animals received injections of an anti-light-chain monoclonal antibody having specificity for an amyloid-related epitope. The reactivity of this monoclonal antibody was not dependent on the V(L) or C(L) isotype of the fibril, but rather seemed to be directed toward a beta-pleated sheet conformational epitope expressed by AL and other amyloid proteins. The amyloidolytic response was associated with a pronounced infiltration of the amyloidoma with neutrophils and putatively involved opsonization of fibrils by the antibody, leading to cellular activation and release of proteolytic factors. The demonstration that AL amyloid resolution can be induced by passive administration of an amyloid-reactive antibody has potential clinical benefit in the treatment of patients with primary amyloidosis and other acquired or inherited amyloid-associated disorders.     

Vitreous involvement in familial amyloidotic neuropathy: a genealogical and genetic study

Extended genealogical studies stretching back to the 17th century were performed concerning the heredity patterns of vitreous involvement in Swedish patients with familial amyloidotic polyneuropathy (FAP). FAP is an autosomal dominant inherited disorder, characterized by extracellular deposition of amyloid and a clinical syndrome of peripheral and autonomic neuropathy. In addition, some patients show typical vitreous opacities. All patients had their origin in a restricted geographical area. Some main patterns arose from this study: 1) Patients who had vitreous opacities as the first symptom of FAP seem to form a separate group, with a distinct age of onset distribution; 2) The familial occurrence of vitreous opacities raises the possibility that other familial factors modify the expression of the FAP gene; 3) The mean age of onset for vitreous opacities is lower for homozygous than for heterozygous patients.     

Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of evidence for immunosuppressive treatment

Cerebral amyloid angiopathy (CAA) is a common but often asymptomatic disease, characterized by deposition of amyloid in cerebral blood vessels. We describe the successful treatment of CAA encephalopathy with dexamethasone in a patient with CAA-related inflammation causing subacute progressive encephalopathy and seizures, which is an increasingly recognized subtype of CAA. The two pathological subtypes of CAA-related inflammation are described and a review of the literature is performed concerning immunosuppressive treatment of CAA-related inflammation with special attention to its pathological subtypes. Immunosuppressive therapy appears to be an appropriate treatment for CAA encephalopathy.     

Amyloid Nephropathy of Ostertag with Special Reference to Renal Glomerular Giant Cells

The pathology of an unusual form of nonneuropathic familial amyloidosis is presented. The disease, occurring in two sisters, is similar to a form of familial amyloidosis described by Ostertag in 1950 and is characterized by progressive renal failure and an autosomal dominant mode of inheritance. Widespread vascular amyloidosis and dense renal glomerular amyloid deposits characterize the disease pathologically. Renal interstitial foam cells and glomerular giant cells were found in the kidneys of one sister. The giant cells, probably of macrophage origin, contain amyloid fibrils within poorly formed non-membrane-bounded cytoplasmic vacuoles. Transitions to well-formed membrane-bounded cytoplasmic vacuoles with nonfibrillar material were also present. It is suggested that these cells function to degrade and resorb amyloid, and that as amyloid is changed to a nonfibrillar state, well-defined membranes can form around the degraded material.     

Differences in the acute phase responses of serum amyloid P-component (SAP) and C3 to injections of casein or bovine serum albumin in amyloid-susceptible and -resistant mouse strains.

In CBA/Ca and C57Bl/Cbi mice, which are susceptible to casein-induced amyloidosis, daily injections of casein caused a marked rise in the level of circulating serum amyloid P-component (SAP), which was sustained while injections continued. In contrast, mice given bovine serum albumin (BSA) injections showed only a small, transient increase in SAP levels. A/J mice, which are relatively resistant to casein-induced amyloidosis, also developed high SAP levels initially, but the increase was not maintained despite continued administration of casein. A/J mice receiving BSA had a slowly progressive rise in SAP which reached the same level as in the casein-treated animals. Administration of colchicine, which prevents casein-induced amyloidosis, suppressed the SAP response to casein in CBA mice. The serum level of the C3 component of complement, which is not an amyloid protein but is an acute phase reactant, also increased following casein injection. The rise in C3 was, however, proportionately less than that of SAP, was less sustained and was scarcely affected by colchicine. The present results therefore demonstrate different patterns in the acute phase response of different proteins in different mouse strains, and suggest that there may be a relationship between sustained high levels of SAP and the deposition of amyloid.     

Seminal vesicle amyloid: the first example of exocrine cell origin of an amyloid fibril precursor.

Amyloid fibrils have been extracted from seminal vesicles, and a dominant 14 kD amyloid fibril protein has been identified. An antiserum to this protein reacted both with amyloid and with epithelial cells in some normal seminal vesicles. These reactions were blocked with seminal vesicle secretion and seminal vesicle amyloid fibril protein, but not by degraded amyloid fibrils or fibril protein from other types of amyloid. It is concluded that seminal vesicle amyloid is derived from secretory proteins of the seminal vesicles. As such, it is the first amyloid described which appears to be the product of an exocrine secretory cell.     

Immunopathological studies on thyroid immunity. IX. Thyroid and renal amyloidosis in thyroglobulin immunized rabbits

In serial studies of immunopathologic changes in an animal model of thyroiditis 52 rabbits were immunized with either bovine, porcine or human thyroglobulin (Tg) in Freund's complete adjuvant, while another 47 animals served as noninjected or adjuvant injected controls. The immunized animals were divided into two groups, one receiving an initial series of only three Tg injections while the other received, in addition, challenging injections over an 8-week period. The immunized animals were killed over a period of 6-34 months after the last Tg injection, and untreated controls were killed at comparable ages. In Tg immunized animals, lymphocytic thyroiditis was encountered in 25 per cent and thyroid amyloid in 17 per cent; glomerular amyloid was encountered in 44 per cent with diffuse lesions in 8 per cent, nodular lesions in 17 per cent and a mixture of the two in 19 per cent. That the thyroid and glomerular hyaline deposits contained amyloid was shown by various histochemical criteria, as well as by the presence of typical fibrils on electron microscopy. Immunohistochemical studies indicated that the amyloid was predominantly of the AA type. Rabbits receiving challenging Tg injections, in addition to the initial series, showed only thyroiditis and nodular glomerular lesions most of which were amyloid. Whilst the vast majority of rabbits with lymphocytic or amyloidotic responses showed both thyroid and renal lesions, a small percentage of animals showed only a lesion of one or the other of these two organs. It is of interest that the thyroid and renal amyloid lesions, described for the first time with induced thyroglobulin immunity, were not detected in other earlier short term investigations.