Fine-resolution mapping by haplotype evaluation: the examples of PFIC1 and BRIC.

Loci for two inherited liver diseases, benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis type 1 (PFIC1), have previously been mapped to 18q21 by a search for shared haplotypes in patients in two isolated populations. This paper describes the use of further haplotype evaluation with a larger sample of patients for both disorders, drawn from several different populations. Our assessment places both loci in the same interval of less than 1 cM and has led to the discovery of the PFIC1/BRIC gene, FIC1; this discovery permits retrospective examination of the general utility of haplotype evaluation and highlights possible caveats regarding this method of genetic mapping.

Benign recurrent intrahepatic cholestasis. Some reflections on a case followed for 20 years.

Benign recurrent intrahepatic cholestasis (BRIC) is a form of cholestasis of obscure aetiology characterized by recurrent episodes of jaundice and itching associated with a morphological picture of pure intrahepatic cholestasis. No effective treatment has yet been found among the many that have been proposed and the invariably benign nature of the condition has been questioned. A case of BRIC followed for a period of 20 years is described. This case is of great interest from these two points of view: 1) the histologic and electron microscopic findings 23 and 41 years after the first episode of cholestasis, respectively, failed to reveal evidence of the possible future development of cirrhosis; 2) treatment with ursodeoxycholic acid proved ineffective both therapeutically and in the prevention of episodes of bile stasis: on the contrary, calculosis of the common bile duct appeared after 8 months from the onset of the treatment.

[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.

[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.

[Liver pathologies due to peroxisome disorders]. / Patologie epatiche da disordini dei perossisomi.

Peroxisomes or microbodies are peculiar subcellular organelles with an important role in the metabolism of a variety of different organic compounds. Particularly they are an important site of bile acids synthesis. Some hepatic diseases, mainly cholestatic, can to be reconnected at disorders of bile acids synthesis by these organelles. From the biochemical point some diseases present alterations of the cholesterol side chain (Zellweger syndrome, pseudo-Zellweger syndrome, infantile Refsum's disease, neonatal adrenoleukodystrophy), other diseases present errors involving the steroid nucleus (familial giant cell hepatitis). Zellweger disease or cerebro-hepato-renal syndrome is characterized clinically by skeletal changes, muscle hypotonia, renal cysts, psychosomatic retardation and persistent cholestasis and from the ultrastructural standpoint by the virtual absence of liver cell peroxisomes. Pseudo-Zellweger disease shows many of the clinical features of Zellweger disease but differs from this condition on account of the presence of abundant peroxisomes in the liver cells. Infantile Refsum's disease and neonatal adrenoleukodystrophy show typical clinical disorders and liver damage leading to cirrhosis. "Familial giant cell hepatitis" is characterized by jaundice from the first days of life, hepatosplenomegaly, cholestasis, lack of physical malformations. The disorder is due to defective biosynthesis of the bile acids with formation of allo-bile acids.

Benign recurrent intrahepatic cholestasis. A clinico-pathologic study.

Authors report 6 cases of benign recurrent intrahepatic cholestasis (BRIC), a rare disease of unknown etiology first described 30 years ago by Summerskill and Walshe, and thought to represent a study model for human cholestasis. Clinical, biochemical and pathologic findings of BRIC are briefly summarized in this paper in order to emphasize some triggering factors of the cholestatic attack (e.g., flu-like episodes and pregnancy), the diagnostic problems and the importance to avoid a surgical procedure. Finally, the 'state of the art' of the pathogenesis of BRIC is briefly summarized.

[Angioimmunoblastic lymphadenopathy with dysproteinemia]. / La linfoadenopatia angioimmunoblastica con disprotidemia.

Angioimmunoblastic lymphadenopathy with dysproteinemia. Angioimmunoblastic lymphadenopathy with dysproteinemia is a lymphomatous-like disease associated with typical anatomopathological features of the lymph nodes and severe dysproteinemia. The clinical course is variable. Acquired immunodeficiency, oral infections, neoplastic development are frequently present. The evolution of the disease is also variable; spontaneous resolution as well as lethal complications are possible. No specific therapy is available. There are conflicting opinions about the nosographic statement of angioimmunoblastic lymphadenopathy among benign lymphadenopathy and lymphomas.

[Angioimmunoblastic lymphadenopathy with dysproteinemia. Personal case reports]. / La linfoadenopatia angioimmunoblastica con disprotidemia. Osservazioni personali.

Angioimmunoblastic lymphadenopathy with dysproteinemia. Case report. We report nine cases of angioimmunoblastic lymphadenopathy with dysproteinemia. Initial symptoms were not specific in any case nor was a specific drug involved as a possible cause. In every case we observed a diffuse enlargement of the lymph nodes and severe dysproteinemia (with hyper or hypo-gammaglobulinemia). Death during the first year was observed for four patients.

[Diphosphonates. Current trends and therapeutic prospects]. / I difosfonati. Attualità e prospettive terapeutiche.

Diphosphonates are compounds characterized by a P-C-P bond. They are thus analogs of pyrophosphate and can be useful for treating several bone diseases. The authors synthetically review the mechanism of action of these drugs and their most important clinical applications. The authors finally mention the interesting therapeutic possibilities deriving from the development of new members of this class.

[Fibrodysplasia ossificans progressiva or Münchmeyer's disease]. / La fibrodisplasia ossificante progressiva o malattia di Münchmeyer.

Fibrodysplasia ossificans progressiva is a heritable and generalized disorder of connective tissue, characterized by the appearance of bony tissue within the striated muscles, tendons and ligaments; moreover, some skeletal abnormalities may also occur, mainly microdactyly of the big toes. This is a very rare disease, which presents in early life; its course is unavoidably progressive, producing a sort of petrifaction of the patient some years after the first symptoms. It is defined as an autosomal dominant trait, being due in most cases to a new mutation. At present no known treatment is available to stop the course of the disease, but sometimes disodium etidronate may be effective in preventing calcification of heterotopic bony tissue.

[Fibrodysplasia ossificans progressiva or Münchmeyer's disease. Personal observation]. / La fibrodisplasia ossificante progressiva o malattia di Münchmeyer. Osservazione personale.

We report here a case of fibrodysplasia ossificans progressiva in a 14-year-old boy, affected from birth by microdactyly of the big toes. This skeletal abnormality also existed in his paternal great-grandfather. When he was 7, some ectopic ossifications occurred and inexorably progressed despite all therapies. Fibrodysplasia ossificans progressiva is a serious and rare disease with a terrible development, leading to a sort of petrifaction of the patient. The lack of knowledge on this ectopic ossification process explains the want of suitable treatments to stop the course of this disease.

[Hypersensitivity angiitis or microscopic polyarteritis nodosa. Recent findings. III. Pathologic anatomy, etiopathogenetic aspects and therapeutic approach]. / Angioite da ipersensibilità o poliarterite nodosa microscopica. Recenti acquisizioni. Nota III. Anatomia patologica, aspetti eziopatogenetici e approccio terapeutico.

Histologically hypersensitivity angiitis produces necrotising inflammation of the small arterial and venous blood vessels. In most cases the inflammatory infiltrate presents leucocytoclasia i.e. nuclear leucocytic detritus. Unlike polyarteritis nodosa, hypersensitivity angiitis does not affect the medium sized arteries though its lesions are produced at the same stage of development. At skin level, the postcapillary venules are the vessels most often affected. Fibrinoid necrosis of the glomerular loops of the kidney may arise and is often accompanied by epithelial crescents. Aetiologically, a variety of agents--bacteria, viruses, drugs, toxic substances--have been held responsible for the disease, though very often the cause cannot be identified. The most widely based on the finding of immunocomplexes, though other immunological disorders might be involved. Treatment involves the elimination of the antigen held responsible, the suppression of the immune response, the removal of circulating immunocomplexes and the use of anti-inflammatory drugs.

[Hypersensitivity angiitis or microscopic polyarteritis nodosa. Recent findings. II. Clinical aspects]. / Angioite da ipersensibilità o poliarterite nodosa microscopica. Recenti acquisizioni. Nota II. Clinica.

Hypersensitivity angiitis is one of the commonest necrotising vasculitides. Given the ubiquitous distribution of the small blood vessels almost any part of the body may be affected. However benign forms predominantly involving the skin are the most common. Forms predominantly involving the viscera and that may prove fatal are rare. Among the polymorphous skin lesions encountered "palpable purpura" is the most common and its palpability is a vital element in differential diagnosis. Among non-cutaneous sites the kidneys are the most frequent and glomerular involvement is the commonest cause of death. Though laboratory tests provide no specific data they may indicate the severity of visceral involvement.

[Angiitis caused by hypersensitivity or microscopic polyarteritis nodosa. Recent findings. I. Nosographic aspects]. / Angioite da ipersensibilità o poliarterite nodosa microscopica. Recenti acquisizioni. Nota I. Aspetti nosografici.

Hypersensitivity angiitis or microscopic polyarteritis nodosa is one of the necrotising angiitis and was not distinguished from classic polyarteritis nodosa until the Fifties. The present study examines the nosographic aspects of necrotising angiitides with reference to the anatomohistological, aetiopathogenic and clinical criteria proposed by various Authors for their identification and with emphasis on the fact that all these factors must be borne in mind for the purpose of diagnosis. The factors that make it possible to distinguish hypersensitivity angiitis from other necrotising angiitides are, at clinical level, the presence of skin lesions, and in anatomohistological terms the involvement of the small blood vessels and leucocytoclasia.