Hepatitis: Invernizzi P

Invernizzi P, Mackay IR. · No affiliation provided · World J Gastroenterol. · Pubmed #18528925 links to  free full text

Abstract: The liver was one of the earliest recognized sites among autoimmune diseases yet autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and their overlap forms, are still problematic in diagnosis and causation. The contributions herein comprise 'pairs of articles' on clinical characteristics, and concepts of etiopathogenesis, for each of the above diseases, together with childhood autoimmune liver disease, overlaps, interpretations of diagnostic serology, and liver transplantation. This issue is timely, since we are witnessing an ever increasing applicability of immunology to a wide variety of chronic diseases, hepatic and non-hepatic, in both developed and developing countries. The 11 invited expert review articles capture the changing features over recent years of the autoimmune liver diseases, the underlying immunomolecular mechanisms of development, the potent albeit still unexplained genetic influences, the expanding repertoire of immunoserological diagnostic markers, and the increasingly effective therapeutic possibilities.

Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. · Institute of Liver Studies, King's College London School of Medicine, London SE5 9RS, UK. · World J Gastroenterol. · Pubmed #18528935 links to  free full text

Abstract: Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases (AiLD), namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children. AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation. PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents as at least two variants, first the classical primary sclerosing cholangitis (PSC) mostly affecting adult men wherein the only (and non-specific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH. Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens, and automated technologies such as ELISAs and bead assays, become available to complement (or even compete with) traditional immunofluorescence procedures. We survey for the first time global trends in quality assurance impacting as it does on (1) manufacturers/purveyors of kits and reagents, (2) diagnostic service laboratories that fulfill clinicians' requirements, and (3) the end-user, the physician providing patient care, who must properly interpret test results in the overall clinical context.

Meda F, Zuin M, Invernizzi P, Vergani D, Selmi C. · Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Milan, Italy. · Autoimmunity. · Pubmed #18176862 No free full text.

Abstract: The widespread use of serum autoantibodies in the practice of clinical hepatology has led to novel challenges in the interpretation of results obtained with routine techniques, such as indirect immunofluorescence (IIF) or with recombinant antigens. In fact, the laboratory methods are often overlooked factors in the interpretation of data by the bedside clinician despite being critical in the interpretation of data. Importantly, the sensitivity and specificity of these serum hallmarks are not defined in all cases. Taken altogether, these observations point towards the need for a systematic discussion of autoimmune serology in the clinical setting of everyday practice. The target of this review article is therefore, to illustrate the current knowledge and available experimental evidence to guide the diagnostic and prognostic decision making in autoimmune and viral chronic liver diseases.

Invernizzi P, Lleo A, Podda M. · Division of Internal Medicine and Liver Unit, San Paolo Hospital School of Medicine, University of Milan, Milan, Italy. · Semin Liver Dis. · Pubmed #17520516 No free full text.

Abstract: Autoimmune liver diseases (ALD) are characterized by immune-mediated injury of bile ducts or hepatocytes, thus including cholangiopathies such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis, and autoimmune hepatitis. Further, ALD variants manifesting with both hepatocellular and cholangiocellular damage are becoming more common. Serum autoantibodies, together with imaging and histology, are critical to the diagnostic process when ALD is suspected. Because an early diagnosis can influence prognosis, the development of sensitive and specific tests for serum autoantibodies should be a priority for researchers to ensure a more efficient noninvasive workup. Little prognostic value has been observed for any of the ALD serum hallmarks, and a vigorous effort to investigate new and old markers should therefore be undertaken in longitudinal studies as in the recent paradigm of PBC-specific antinuclear antibodies. We review herein the numerous ALD screening tests available in routine and specialized laboratories and comment on their significance in clinical practice.

Zuin M, Giorgini A, Selmi C, Battezzati PM, Cocchi CA, Crosignani A, Benetti A, Invernizzi P, Podda M. · Department of Medicine, Division of Internal Medicine, San Paolo School of Medicine, University of Milan, Milan, Italy. · Dig Liver Dis. · Pubmed #18294936 No free full text.

Abstract: Buprenorphine is a semi-synthetic opioid derivative commonly used in the treatment of heroin addiction. Life-threatening complications have been described following overdoses while few cases of hepatotoxicity due to drug use at therapeutic doses have been recently described in hepatitis C virus carriers. In these cases, however, histological assessment was not exhaustive and no extra-hepatic organ failure was observed. We describe herein a case of acute liver and kidney failure in a patient with previously latent hepatitis C virus chronic infection following recommended doses of buprenorphine. Histology did not demonstrate any feature compatible with hepatitis C virus reactivation or liver cirrhosis and suspension of the treatment led to the resolution of both liver and kidney failure. Causality criteria fulfillment indicates a high probability of buprenorphine-induced liver toxicity. No signs of pre-existant kidney impairment or of pre- or post-renal causes were observed. Since buprenorphine is metabolized through cytochrome P450 3A4, we genotyped six genetic polymorphisms previously described in poor metabolizers but could not confirm these pharmacogenetic bases in this case. In conclusion, we surmise that buprenorphine at suggested doses can induce liver and kidney failure in susceptible individuals, possibly through direct mitochondrial toxicity.

Oertelt S, Rieger R, Selmi C, Invernizzi P, Ansari AA, Coppel RL, Podda M, Leung PS, Gershwin ME. · Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA. · Hepatology. · Pubmed #17326160 No free full text.

Abstract: The antimitochondrial response in primary biliary cirrhosis (PBC) is the most highly directed and specific self-reacting antibody in human immunopathology. Originally, antimitochondrial antibodies (AMAs) were detected by indirect immunofluorescence (IIF) and found in approximately 90% of well-documented patients with PBC. The introduction of recombinant autoantigens and the use of immunoblotting have increased the sensitivity and specificity of AMAs, and they are now considered positive in approximately 95% of patients with PBC. Clearly, accurate autoantibody detection represents one of the fundamental requirements for reliable diagnostics in autoimmunity. To address the 5% of AMA-negative patients with PBC, we have generated and validated a bead assay for the detection of AMA. We enrolled 120 patients with PBC, including a non-random group of 30 rigorously proven AMA-negative patients, 50 healthy subjects, and 74 controls with autoimmune diseases (18 with primary sclerosing cholangitis, 16 with autoimmune hepatitis, and 40 with systemic lupus erythematosus). Individual bead assays were done with the three mitochondrial autoantigens, PDC-E2, BCOADC-E2, and OGDC-E2. As expected, 90 of 90 previously known AMA-positive patients remained positive with this assay but, interestingly, 20% of the rigorously defined AMA-negative patient group had antibodies to one or more of the mitochondrial autoantigens. Furthermore, 100% of these newly detected AMA-positive patients were anti-nuclear antibody (ANA) positive. CONCLUSION: The development of this assay reflects the potential for automated detection with rapid and reliable assaying and further highlights the diminished number of truly AMA-negative PBC patients.

Invernizzi P, Miozzo M, Battezzati PM, Bianchi I, Grati FR, Simoni G, Selmi C, Watnik M, Gershwin ME, Podda M. · Department of Internal Medicine University of Milan, Via di Rudinì 8, 20142 Milan, Italy. · Lancet. · Pubmed #14975617 No free full text.

Abstract: The mechanisms that cause the female predominance of primary biliary cirrhosis (PBC) are uncertain, but the X chromosome includes genes involved in immunological tolerance. We assessed the rate of X monosomy in peripheral white blood cells from 100 women with PBC, 50 with chronic hepatitis C, and 50 healthy controls, by fluorescence in-situ hybridisation. Frequency of X monosomy increased with age in all groups, but was significantly higher in women with PBC than in controls (p<0.0001); age-adjusted back-transformed mean frequencies were 0.050 (95% CI 0.046-0.055) in women with PBC, 0.032 (0.028-0.036) in those with chronic hepatitis C, and 0.028 (0.025-0.032) in controls. We suggest that haploinsufficiency for specific X-linked genes leads to female susceptibility to PBC.

Crosignani A, Invernizzi P, Ferrari R, Manzin A, Bruno S, Zuin M, Bianchi FB, Podda M. · Department of Internal Medicine, School of Medicine San Paolo, University of Milan, Italy. · Ital J Gastroenterol Hepatol. · Pubmed #10091106 No free full text.

Abstract: Acute and severe impairment of liver function with jaundice and ascites occurred in two out of seven patients with chronic hepatitis D during interferon alpha administration (10 MU three times a week). Both of them were young women with histological diagnoses of moderate to severe chronic hepatitis and cirrhosis with no signs of portal hypertension. Only a slow and partial recovery was observed after interferon withdrawal. Autoantibodies against basal cell layer tested positive in these two patients. In the remaining five patients with hepatitis D who did not experience liver impairment during interferon administration, basal cell layer antibodies were found only in one case. We conclude that severe decompensation of liver cirrhosis related to hepatitis D may occur during interferon administration. Positivity of basal cell layer antibodies may be associated with the risk of developing such an adverse event but our data are not sufficient to prove this association.