[Intrahepatic cholestasis caused by biochemical errors of bile acids. Part I --Nosographic, pathogenetic, diagnostic features]. / Colestasi intraepatiche da errori biochimici degli acidi biliari. Parte I--Aspetti nosografici, patogenetici, diagnostici.

Intrahepatic cholestasis occurs in certain conditions characterized by a biochemical error of bile acid metabolism, resulting from a disorder of the hepatic canalicular system responsible for synthesis or secretion of the bile acids. As regards the pathogenesis of these "primary" forms of cholestasis, it must be remembered that cholestasis represents the outcome of various factors capable of interfering with the mechanism of bile flow. Therefore the factors known to be involved in cholestasis, such as the metabolic steps in bile acid metabolism, the cytoplasmic membrane, the mitochondria, the cytoskeleton of the liver cell, the intercellular junctions, the physicochemical state of the canalicular bile, are discussed briefly. The diagnostic and clinical aspects of cholestasis with reference to the clinical symptoms, laboratory findings and to role of liver biopsy are synthesized, and the essential criteria for a methodological approach to cholestasis are proposed.

[Intrahepatic cholestasis due to biochemical errors of bile acids. II. Clinical and therapeutic aspects]. / Colestasi intraepatiche da errori biochimici degli acidi biliari. Parte II--Aspetti clinici e terapeutici.

Within the "primary" cholestasis we can discriminate "essential" forms due to an endogenous biochemical error of bile acid metabolism and/or secretion and "conditioned" forms, in which a known precipitating factor is required to elicit the functional disorder responsible for cholestasis. Among the essential forms of cholestasis must be included benign recurrent intrahepatic cholestasis or Summerskill-Walshe disease, Aagenaes disease, progressive familial intrahepatic cholestasis or Byler's disease, and forms due to disorders of the peroxisomes. Benign recurrent intrahepatic cholestasis, the best known form, is characterized by recurrent episodes of itching and jaundice with an acute onset separated by symptom-free intervals, which shows no tendency to progress to liver failure. The conditioned cholestasis group comprises cholestasis of pregnancy and drug-induced cholestasis. Benign recurrent cholestasis of pregnancy is a form induced "by" pregnancy and not a form occurring "in" pregnancy, such as cholestasis due to hepatitis, to primary biliary cirrhosis, to cholelithiasis. Drug-induced cholestasis is a chapter of great clinical relevance: forms due to steroid hormones and due to phenothiazines are discussed.

[Fanconi-Zinsser disease]. / La malattia di Fanconi-Zinsser

Fanconi-Zinsser's disease is a serious involutive myelopathy responsible for pancytopenia, hyperpigmentation, oralplakia and onychodystrophy, together with lesser dysmorphisms in many cases. The marrow blood picture is reminiscent of the better-known Fanconi's disease, while the skin and mucosa picture is similar to that of congenital dyskeratosis - hence the combined name. A typical case, but complicated by Lewandowsky's disease for the first time in the literature, is presented. Papova-virus was noted in the typical verrucae. The modern "pathology due to genome instability" is examined. Lewandowsky's disease is regarded as a familial form and precancerous, owing to its possible Bowenoid transformation. The association is seen as particularly significant in stressing the disorder of the immunocompetent syste, this being most evident from the finding of serum anti-red-cell auto-antibodies and a deficiency of T lymphocytes. Fanconi-Zinsser's disease has only been reported 21 times in the literature, mostly in males. Incomplete forms are, however, noted in relatives, suggesting that it originates in a genetic disorder whose transmission modality is not clear, though incomplete dominance is suspected. Genome instability is probably responsible behind the onset of the disease and its neoplastic complications - these being also feature of other forms provoked by such instability, such as Bloom's syndrome and ataxia telengiectasia. Fanconi's disease also has marked neoplastic tendencies. Clinically, Fanconi-Zinsser's disease can be classified as distinct, since it has signs and an evolutive modality that distinguish it from Franconi's disease, Estren-Damesheck's syndrome and amegakaryocytic thrombocytopenia. Genetically, it can be seen that all these diseases are referable to "pathology due to genome instability".

[Adriamycin in chemotherapy of solid tumors]. / L'adriamicina nella chemioterapia dei tumori solidi

From one to eight, 7 or more day spaced, three-day 0,5 mg/kg/day cycles of adriamycin (an anthracycline antiblastic very similar to daunomycin) were administered to 50 adults with various solid tumour forms. Toxic signs were constant and sometimes compelled abandonment. The main residual signs were leucopenia, alopecia and stomatitis. The drug also displayed a cardiotoxic effect, though this was less than observed with daunomycin. It is felt that the theoretical interest aroused in adriamycin as an inhibitor nucleic acid systhesis, together with its marked anti-neoplastic efficacy in the experimental animal, have been betrayed by this performance in the management of solid tumors.

[The lymphoid-like cells in blastic transformation of chronic myeloid leukemia]. / Le cellule "lymphoid like" nella trasformazione blastica della leucemia mieloide cronica.

The natural history of chornic myeloid leukaemia (CML) usually ends with a blastic transformation (BT). In 30% of cases, BT displays the cytomorphological, cytochemical, immunological and biochemical features and the response to therapy observed in acute lymphoblastic leukaemia (ALL). The presence of lymphoid-like cells in a blood disease classically interpreted as a disorder of the myeloid strain led to the suggestion that CML is a disease of a stem cell capable of displaying both myeloid and lymphoid characters. It is thought that this is due to the fact that the Ph1 alteration strikes a premyeloid and prelympoid stem cell that presents myeloid features in the chronic stage of CML and in myeloblastic BT, whereas it displays lymphoid characteristics in the lymphblastic BT of CML and Ph1+ ALL. This fact lends support to the unicystic haematopoietic theory of Ferrata. Reference is made to a case in which the BT of CML was marked by the predominant presence of cells with a lymphoblastic appearance.

[Takayasu-Onishi arteritis. Current etiopathogenetic aspects]. / Arterite di Takayasu-Onishi. Aspetti exiopatogenetici recenti

By Takayasu-Onishi's arteritis is meant an arteritic process with unknown aetiology which electively affects young women, seemingly of prevalently Asiatic stock. The disease concerns almost exclusively large elastic arteries and presents clinically with early preocclusive symptomatology followed, after a varying period, by a picture of obstructive angiopathy. Here, the most recent aetiopathogenetic findings are considered. The disease's predilection for the young female, together with certain clinical and experimental observations, suggest that a dysendocrine condition may have some pathogenetic responsibility, at least in a favourable sense; this responsibility is documented by the finding of high levels of oestrogenuria during the entire cycle in patients suffering from the disease. On the other hand, the angiopathy localization in the large elastic arteries and in certain segments of the aortic arch and epiaortic trunks means that the role of topographic moments whould not be underestimated. As regards infectious factors, the tubercular and streptococcic continue to be of great importance even today. Neither acts directly, however, but by way of an abnormal immunitary reaction which they seem able to trigger off. The infectious moment would thus appear to be related to the immunitary moment, and the latter would seem to play the part of perpetuating the pathological vascular involvement promoted by contact of the organism with the aetiological agent.

[Takayasu-Onishi arteritis. II. Relations of Takayasu-Onishi arteritis with other non-specific arteritides]. / Arterite di Takayasu-Onishi. Nota II. Rapporti dell'arterite di Takayasu-Onishi con altre arteriti non specifiche

Takayasu-Onishi arteritis (T.O.) is similar to Hutchison-Horton arteritis (H.H.) on histological, clinical, laboratory, and pathogenetic grounds. Both probably depend on immunitary dysreactivity, their different clinical expression being attributable to differences in the district involved and the age of the subject. Both are preceded or accompanied by rheumatism. An interesting relation can be made out between temporal arteritis and "rheumatic polymyalgia" or, more aptly, "rhizomelic polymyalgia" (Ballabio, 1975). The latter (of rheumatic origin) may accompany arteritis - Hamrin, indeed, has suggested their unification in the description "arteritic polymyalgia". It is uncertain whether vasculopathy in the course of collagen disease, rheumatic arteritis, and polyarteritis nodosa can be identified with T.O., even though a common immunological basis can be made out. The difference between T.O. and thromboangiitis obliterans, on the other hand, is quite clear at the present time.

[Osteopetrosis (Albers-Schoenberg disease). III. Current nosographic aspects and relations to other condensing osteopathies]. / L'osteopetrosi (malattia di Albers-Schönberg) Nota III. - Aspetti nosografici attuali e rapporti con altre osteopatie condensanti

A malignant paediatric variety and an adult variety of Albers-Schönberg disease are normally distinguished. On the basis of recent findings and personal observation it would appear advisable to accept two different courses of Albers-Schönberg disease in adults: one resembling the malignant infant form and the other with slow, practically asymptomatic (apart, obviously, from the skeletal lesions) course allowing for prolonged survival. This classification is of considerable practical importance for prognosis and therapeutic purposes. Other hereditary-familial and constitutional condensing osteopathy pictures exist that present radiological stigmata similar to those seen in Albers-Schönberg disease. The interest of the relations between A-S disease and certain of these condensing osteopathic conditions is obvious.

[Hutchinson-Horton giant cell arteritis and rhizomelic polymyalgia. II. Rhizomelic polymyalgia. Arteritic polymyalgia]. / L'arterite gigantocellulare di Hutchinson-Horton e la polimialgia rizomelica. Nota II. La polimialgia rizomelica. La polimialgia arteritica.

Rhizomelic polymyalgia is an inflammatory form. Its site of choice is the shoulder girdle and it is almost solely observed in elderly subjects. An account is given of its epidemiological, clinical and anatomopathological aspects. Its aetiology is also discussed with particular reference to its possible immunological or vascular origin. The rheumatic symptoms of rhizomelic polymyalgia are similar to those observed in temporal arteritis. Since artery lesions are found in most cases, the name "polymyalgia arteritica" has been suggested as an alternative clinical description by Hamrin .

[Hutchinson-Horton giant cell arteritis and rhizomelic polymyalgia. III. Current pathogenetic and nosographic aspects]. / L'arterite gigantocellulare di Hutchinson-Horton e la polimialgia rizomelica. Nota III. Aspetti patogenetici e nosografici attuali.

There is much evidence to suggest that temporal arteritis and rhizomelic polymyalgia are both immunological diseases. The classic results of experimental pathology are discussed, together with the relations between rhizomelic polymyalgia and both virus hepatitis B and the HLA system. From the clinical standpoint, it is now agreed that differences in individual response may lead to either a synovial or an arteritic response in both forms. Their association in what Hamrin has called "polymyalgia arteritica" is also common.

[Hypereosinophilias of the blood. I. Eosinophilic granulocytes]. / Le ipereosinofilie del sangue. Nota I. Il granulocita eosinofilo.

A knowledge of eosinophil granulocytes is indispensable for the study of hypereosinophilia. For this reason, the most recent findings relating to eosinophil morphology, production/regulation mechanism, and function are reported. Particular attention is given to enzyme populations, local control mechanisms and eosinophil cell surface receptors. Among the various enzymes present in the eosinophil, major basic protein (MBP), with its capacity to damage the cells of many organs, plays an important part; other enzymes include eosinophil peroxidase (EPO), arylsulphatase B, phospholipase D, histaminase and cationic proteins (ECP). Factors influencing eosinophil tissue concentrations and mode of action are considered. Recent findings agree on the role of eosinophils in immunological reactions and parasitic infestations: eosinophil plays a part in an immunological physiopathological sequence: it may, act as a killer cell with selective action against invading parasites, or it may be an immune modulator, anti-inflammatory cell able to surround inflammatory reactions and prevent them from spreading.

[Blood hypereosinophilias. IV. Symptomatic hypereosinophilias: connective tissue diseases, neoplasms, blood diseases, various causes]. / Le ipereosinofilie del sangue. Nota IV. Ipereosinofilie sintomatiche: malattie del connettivo, neoplasie, affezioni emopatiche, cause varie.

Among the symptomatic hypereosinophilias and apart from pathologies covered in Note III, diseases of the connective tissue, neoplasias, blood diseases and other conditions are also examined. Two connective tissue diseases often accompanied by hypereosinophilias are Churg and Strauss angiitis and eosinophilic fascitis. Churg and Strauss angiitis (of which 2 personal cases are reported) is a systemic vasculitis usually seen in combination with bronchial asthma and haematic eosinophilia. Eosinophilic fascitis is quite rare and poorly understood. Its symptoms include hardening of the skin and eosinophilia and it is difficult to differentiate from progressive systemic sclerosis. The possible reasons why hypereosinophilia sometimes accompanies benign and more often malignant tumours are discussed. The pathogenesis of the hypereosinophilias encountered in diseases of the blood is still controversial. One hypothesis is that hypereosinophilia is an intrinsic symptom of the blood disease, others believe it to be an immunological response. In this context two personal cases are reported as examples: one of hypereosinophilia in a malignant non-Hodgkins lymphoma, the second in an IgG plasmacytoma. Particular attention was paid to the hypereosinophilia that accompanies the rare blood disease known as angioimmunoblastic lymphoadenopathy with dysproteinaemia (LAID) of which a personal case is reported.

[Gilbert's jaundice. Current clinico-nosographic, physiopathological and therapeutic aspects. III. Therapeutic action of enzyme inductors with reference to unconjugated bilirubin icterus]. / Gli itteri di Gilbert. Attuali aspetti clinico-nosografici, fisiopathologici e terapeutici. Nota III. - Azione terapeutica degli induttori enzimatici nei confronti degli itteri a bilirubina non coniugata

The value of phenobarbital in the treatment of free bilirubin icterus is demonstrated by a series of clinical experiments in which the drug was administered to patients with bilirubinaemia, even at high levels, the situation being brought back to normal within about two weeks. The percentage excreted with the urine in a conjugated form of various drugs proved higher in subjects treated with phenobarbital than in controls, thus proving that the drug acts as an enzymic inductor. Moreover it is ineffective in patients genetically lacking in the capacity to synthesize glycuronyltransferase. The induction of this latter enzyme, however, does not exhaust the effects of the barbiturate for it has been shown that phenobarbital is capable of speeding up the disappearance of exogenous bilirubin from the plasma in animals, of stimulating bile flow and increasing uptake of the pigment by the liver. The increase in bile flow is of the order of 30% and takes place by way of a modification in the flow fraction independent of bile salts. It would also appear that the drug is capable of increasing the activity of 7-alpha-hydroxylase, an enzyme that represents the rate limiting step in the synthesis of biliary salts. Other drugs commonly used in the treatment of free bilirubin icterus such as ethanol, rifampicin and uridindiphosphoglucose are considered. Finally the case of a female patient who from birth had presented persistent free bilirubin icterus of about 8 mg% is reported. After 14 days treatment with phenobarbital (100 mg X 2) blood levels of the pigment had returned to normal.

[Osteopetrosis (Albers-Schönberg disease). I. Clinico-radiological and pathogenetic aspects]. / L'osteopetrosi (malattia di Albers-Schönberg) nota I Aspetti clinico-radiologici e patogenetici

An account is given of recent clinical and radiological findings with respect to Albers-Schönberg disease. Reference is made to its hereditary transmission modality and clinical picture (skeletal lesions and haematological distress), and to its radiological aspects. Suggestions are made with respect to the aetiopathogenesis of disease. Stress is laid on the as yet undefined mechanism of "genotypical condensing dysplasia". The relation between osteopetrosis and thyrocalcitonin is discussed, though no definite conclusions could be drawn from the hormone levels determined in a personal series.

[Osteopetrosis ( Albers-Schönberg disease ). II. Personal contribution]. / L'osteopetrosi (malattia di Albers-Schönberg). Nota II Contributo personale

Five cases of marble bones in two families living near Brescia are presented. Case 1 (42-yr-old female) was a typical malignant form with deep and extensive eburnation, many pathological fractures, concomitant osteitis and the formation of many fistulae, massive spleen enlargement and infarct, and marked anaemia with clear signs of extra-medullary haemopoiesis. The patient died 5 yr after her first admission. Two of her brothers had had an identical, fatal form. Case 4 (28-yr-old male) was much the same: virtually general osteosclerosis despite the difference in age, marked spleen enlargement, a history of fractures, serious anaemia and extramedullary haemopoiesis. Benign pictures were seen in cases 2 and 3 (73- and 68-yr-old females). In case 5 (25-yr-old male), typical bone condensation was the only significant pathological sign. It is suggested that this, too, may be seen as a "benign" form.

[Hutchinson-Horton giant cell arteritis and rhizomelic polymyalgia. I. Hutchinson-Horton arteritis]. / L'arterite gigantocellulare di Hutchinson-Horton e la polimialgia rizomelica. Nota I.- L'arterite di Hutchinson-Horton.

Temporal arteritis (also known as Horton's or giant cell arteritis) is a panarteritis of the large and medium-calibre cranial vessels. An account is given of its epidemiological, clinical and anatomopathological aspects and its involvement of the locomotor apparatus (Horton's rheumatism). Reference is also made to the close relationship between temporal arteritis and pulseless disease. Some workers are of the opinion that they share the same aetiology, and that their clinical expression in different areas is dictated by age and constitutional factors.

[Hypereosinophilia of the blood. II. Classification. Benign essential hypereosinophilia. Eosinophilia caused by systemic eosinophilic hemopathies]. / Le ipereosinofilie del sangue. Nota II. Nosografia. Ipereosinofilie benigne essenziali. Ipereosinofilie da emopatia sistemica eosinofila.

Following a previous note on the latest development in the study of eosinophilic granulocytes, a nosographic classification scheme is proposed for the problematic group of haematic eosinophilias. The scheme is based on the division of hypereosinophilias into three basic groups: benign idiopathic hypereosinophilias, hypereosinophiliasis caused by systemic eosinophilic blood diseases and symptomatic hypereosinophilias. Two rare events, hereditary familial eosinophilia and bening, non-familial idiopathic eosinophilia may be added to the benign idiopathic hypereosinophilias group. The group of hypereosinophilias caused by systemic eosinophilic blood diseases is still controversial and difficult to interpret. Particular attention is paid to the so-called "idiopathic hypereosinophilic syndrome" (HES), an umbrella term under which there is a current tendency to group a heterogeneous series of disorders characterised by long-lasting hypereosinophilia where there is no known reason for the increased eosinophilic granulocyte rate. Clinical and physiopathological features are then described to decide whether a given condition lies within the scope of this still little known syndrome.

[Blood hypereosinophilias. III. Symptomatic hypereosinophilias: allergic, cutaneous, parasitic, infective, pulmonary and gastro- intestinal diseases]. / Le ipereosinofilie del sangue. Nota III. Ipereosinofilie sintomatiche: malattie allergiche, cutanee, parassitarie, infettive, polmonari, gastroenteriche.

The most frequently observed of the symptomatic hypereosinophilias are those caused by allergic, cutaneous, parasitic, infectious, pulmonary and gastroenteric conditions. Among the allergic conditions, particular attention is paid to the hypereosinophilias caused by allergic asthma, gastroenteritis and reactions to drugs. The most common skin conditions linked to hypereosinophilias such as bullous dermatites and angio-oedema are considered. Turning to the parasitic conditions, the various types of parasite that may produce hypereosinophilias by infesting the organs are examined. The aetiology of tropical eosinophilias and the pathogenetic mechanism that may trigger hypereosinophilias are discussed. It has been thought advisable to group the lung pathologies associated with hypereosinophilias under a separate heading, despite the indubitable importance of the allergic element in these events. Among gastroenteric conditions, the one considered is eosinophilic gastroenteritis whose clinical, anatomopathological and aetiopathogenic features are still not quite clear. Examples of certain forms of secondary hypereosinophilias are given in the form of four unusual personal cases of bronchial asthma, filariasis, an exceptional infestation by Hypoderma bovis and eosinophilic gastroenteritis.

[Amyloidosis. II. Current pathogenetic and clinico-nosographic aspects]. / L'amiloidosi. Nota II. Aspetti patogenetici e clinico-nosografici attuali.

Amyloidosis is due to the overproduction of a precursor protein and its conversion into products capable of polymerisation into fibrils. The primary form, or that associated with multiple myeloma or Waldenström's macroglobulinaemia, marked by the presence of protein AL, includes the overproduction of Ig light chains followed by conversion on the part of lysosome enzymes. The forms can thus be classified as immunoproliferative diseases (plasma-cell dyscrasias). Secondary amyloidosis is primarily associated with neoplasia or chronic inflammation. Its biochemical label is the AA protein. Initially, there is overproduction of protein SAA, while the formation of AA-amyloid fibrils may theoretically be attributed to a variety of factors: changes in the amount of circulating SAA, the presence of amyloidogenetic SAA, variations in the activity of SAA catabolic systems, insufficient removal of acculated fibrils. The way in which the immunocompetent system intervenes is a controversial subject. Lesser froms of amyloidosis are known in which there are local deposits of amyloid: APUD-amyloidosis, amyloidomas. In some forms, the features of systemic accumulation are maintained, but only one organ is primarily involved. They are rarely of clinical significance (e.g. senile amyloidosis). Current biochemical techniques enable a clinical and nosographic distinction to be drawn between an Ig (AL)-amyloidosis and non-Ig (AA, APUD and AS) forms.

[Amyloidosis. I. Recent findings concerning amyloid substance]. / L'amiloidosi. Nota I. Recenti acquisizioni sulla sostanza amiloide.

The considerable progress made recently in the study of amyloid substance have led to the identification of numerous organised protein components in typical microfibrillar structures. In spite of the biochemical heterogeneity of fibril proteins, it is still possible to find similar chemicophysical and tintorial features in the various types of amyloid, probably due, at least in part, to the common Beta type molecular configuration, a structure proper to fibril proteins. In so-called primary amyloidosis and in that associated with myelomatous diseases, the principal protein component consists of AL protein, correlated with the light immunoglobulin chains, with which analogies have been observed both in the amino acid sequence and in antigenic characteristics. In secondary amyloidosis, AA protein, which is unrelated to immunoglobulins or other known human proteins, is prevalent. AA protein probably derives from a serum globulin, SAA, whose blood levels increase during numerous pathological processes, particularly in those of neoplastic or inflammatory type. The origin of serum protein, which might be either a normal tissue component released under stimulus or a reagent of the acute phase synthesised ex novo, and its function, which is probably of immunomodulator or more specifically immunosuppressive type, are still to be defined. In all forms of amyloidosis studied, a common observation is the presence of AP protein, organised in pentagonal structures. This protein would appear to derive from a serum component defined as SAP, with a marked affinity for amyloid fibrils. Also identifiable are other forms of amyloid such as APUD-amyloid, which probably derives from polypeptide hormones, and AS amyloid, which is present in some organs of elderly patients and is biochemically identifiable at cardiac level with A(SCA) protein. Still awaiting definition in amyloid tumours or amyloidomas is the precise chemical composition of deposited proteins.