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Hepatology – A clinical textbook gives a comprehensive overview on the epidemiology, virology, and natural history of all hepatitis viruses including hepatitis A, D and E. Subsequent chapters cover all major aspects of the management of hepatitis B and C including coinfections with HIV and liver transplantation.
Extrahepatic Manifestations of Chronic HCV 323 15 Extrahepatic Manifestations of Chronic HCV Albrecht Böhlig, Karl-Philipp Puchner and Thomas Berg Introduction Patients with chronic hepatitis C virus (HCV) infection are at risk of a variety of extrahepatic manifestations (EHMs) (Table 1) – up to 70% of patients develop HCV EHMs according to large cohort studies (Cacoub 2000, Cacoub 1999) EHMs may often be the first and only clinical sign of chronic hepatitis C infection Evidence of HCV infection should always be ruled out in cases of non-specific chronic fatigue and/or rheumatic, hematological, endocrine or dermatological disorders The pathogenesis of EHM is still not fully understood although most studies suggest that the presence of mixed cryoglobulinemia, particularly HCV lymphotropism, molecular mimicry and non-cryoglobulinemic autoimmune phenomena constitute the major pathogenic factors (Ferri 2007) Nevertheless, the pathogenesis and epidemiology of many EHMs require further investigation (Figure 1) Our aim is to give a brief insight into the epidemiology, pathogenesis, clinical relevance and therapeutic management of HCV-associated EHM (Zignego 2007a) Mixed cryoglobulinemia Cryoglobulinemia refers to the presence of abnormal immunoglobulins in the serum, which have the unusual property of precipitating at temperatures below 37°C and redissolving at higher temperatures The phenomenon of cryoprecipitation was first described in 1933 (Wintrobe 1933) Cryoglobulins (CGs) are nowadays classified into three types (Table 2) based on their clonality Type II CG and type III CG, consisting of monoclonal and/or polyclonal immunoglobulins, are prevalent in patients with chronic HCV infection, while type I CGs, consisting exclusively of monoclonal components, are mostly found in patients with lymphoproliferative disorders (multiple myeloma, B cell lymphoma, Waldenström macroglobulinemia) Type II or type III mixed cryoglobulinemia is found in 19%-50% of patients with chronic HCV but leads to clinical manifestations through vascular precipitation of 324 Hepatology 2015 immunocomplexes in only 30% of them (Lunel 1994, Wong 1996) Asymptomatic mixed cryoglobulinemia during the course of chronic HCV infection may evolve into symptomatic disease Patients with symptomatic mixed cryoglobulinemia exhibit higher cryoglobulin concentrations (cryocrit >3%) (Weiner 1998) and lower concentrations of complement factors C3 and C4 Thus CG-triggered complement activation may constitute a key incidence in cryoglobulinemia-derived pathogenesis Factors that seem to favour the development of MC are female sex, age, alcohol intake (>50g/d), advanced liver fibrosis and steatosis (Lunel 1994, Wong 1996, Saadoun 2006) Table Extrahepatic manifestations of chronic hepatitis C infection Organ/System involved Manifestation Endocrine • Autoimmune thyroidopathies (in particular, Hashimoto thyroiditis) • Insulin resistance/diabetes mellitus* • Growth hormone (GH) insufficiency • Vitamin D deficiency • Rheumatic disorders • • • • • • • • Mixed cryoglobulinemia* Cryoglobulinemic vasculitis* Peripheral neuropathy* Membrano-proliferative glomerulonephritis (GN)* Membranous GN* Rheumatoid arthralgias/oligopolyarthritis Rheumatoid factor positivity* Sicca syndrome Hematologic disorders • • • • Lymphoproliferative disorders/Non-Hodgkin Lymphomas* Immune thrombocytopenic purpura (ITP) Monoclonal gammopathies* Autoimmune hemolytic anemia Dermatologic disorders • • • • Palpable purpura Porphyria cutanea tarda (PCT) Lichen planus Pruritus Central nervous system disorders • Chronic fatigue*, subclinical cognitive impairment, psychomotoric deceleration, symptoms of depression* • Neurocognitive disorders Miscellaneous • Myopathy • Cardiomyopathy/Myocarditis • Idiopathic pulmonal fibrosis *Associations based on strong epidemiological prevalence and/or clear pathogenetic mechanisms Extrahepatic Manifestations of Chronic HCV 325 Table Types of cryoglobulinemia Type Clonality Type I Monoclonal immunoglobulins (IgG or IgM) Type II Polyclonal immunoglobulins (mainly IgG) and monoclonal IgM with rheumatoid factor activity (RF) Type III Polyclonal IgG and IgM Autoimmune haemolytic anaemia D GHInsuffiency Myocarditis Myopathy Non-cryogloblinaemic neuropathies Idiopatic pumlmonary fibrosis C Thrombocytopenia Autoimmune thyroiditis Diabetes mellitus II Rheumatoid arthritis Non-cryoglobulinaemic GN Sicca syndrom B Porphyria cutanea tarda Lichen planus Lymphoproliferative disorders A MC-related disorders Figure Schematic representation of EHM categories (modified after Zignego 2007a) A) Associations with strong epidemiological evidence and clear pathogenetic mechanisms; B) Associations with high prevalence, but unclear pathogenetic mechanisms; C) Associations for which the high prevalence in HCV collectives could be due to HCV infection and/or confounding factors; D) Anecdotal observations Diagnosis Detection of CG is carried out by keeping patient serum at 4°C for up to days When cryoprecipitate is visible, CG can be purified and characterized using immunofixation electrophoresis In case of evidence of mixed cryoglobulinemia in HCV-positive patients, cryoglobulinemic syndrome needs to be looked for Vigilant monitoring is required, as asymptomatic mixed cryoglobulinemia patients may develop MC-related disorders in the course of the disease The diagnosis of the MC syndrome is based on serologic, pathologic and clinical criteria (Table 3) 326 Hepatology 2015 Table Diagnostic criteria of cryoglobulinemic syndrome Serologic Histopathologic Clinical • C4 reduction • Positive rheumatoid factor (RF) • CGs, type II or III • HCV antibodies • Leukocytoclastic vasculitis • Purpura • Monoclonal B cell infiltrates • Fatigue • Arthralgia • Membranoproliferative GN • Peripheral neuropathy In the presence of mixed CG, low C4 counts, leucocytoclastic vasculitis and purpura, a definite symptomatic MC can be diagnosed Rheumatoid factor (RF) determination constitutes a reliable surrogate marker for detection of CG Finally, presence of CG may impair HCV RNA determination as viral RNA can accumulate in precipitated cryocrit (Colantoni 1997) Clinical presentation HCV-related MC proceeds mostly asymptomatically and has no significant influence on the course of chronic liver inflammation On the other hand, symptomatic mixed cryoglobulinemia is associated with higher mortality (Ferri 2004) Systemic vasculitis HCV-related vasculitis relies on a deposition of immunocomplexes containing CGs, complement and large amounts of HCV antigens in the small- and medium-sized blood vessels HCV accumulates in the CG immunoglobulins Pathohistological findings reveal a leucocytoclastic vasculitis (Agnello 1997) The most common symptoms of mixed cryoglobulinemic vasculitis are weakness, arthralgia and purpura (the Meltzer and Franklin triad) Mixed cryoglobulinemic vasculitis may also lead to Raynaud’s Syndrome and Sicca Syndrome, glomerulonephritis and peripheral neuropathy Renal impairment The predominant renal impairment associated with mixed cryoglobulinemia is the membranous proliferative glomerulonephritis (MPGN), characterized in most cases by proteinuria, mild hematuria and mild renal insufficiency The presence of kidney impairment is considered to be a negative prognostic factor in the course of the disease (Ferri 2004) In 15% of patients, MC-related nephropathy may progress to terminal chronic renal failure requiring dialysis (Tarantino 1995) Peripheral neuropathy Peripheral neuropathy, on the basis of endoneural microangiopathy, constitutes a further typical complication of mixed cryoglobulinemia MC-related neuropathy, presenting clinically as mononeuropathy or polyneuropathy, is mostly sensory and is characterized by numbness, burning skin, a crawling sensation, and pruritus, predominantly in the hands and feet (Tembl 1999, Lidove 2001) Epidemiological data from Italy suggests that peripheral neuropathy is the second most common symptom after the Meltzer and Franklin triad in patients with symptomatic HCVassociated mixed cryoglobulinemia (Ferri 2004) Extrahepatic Manifestations of Chronic HCV 327 Cirrhosis The causal association between CG and progression of liver fibrosis suggested by numerous authors was not confirmed in a published 10-year prospective study The 10-year rates of progression to cirrhosis were similar in cryoglobulinemic and noncryoglobulinemic HCV-infected patients (Vigano 2007) From this, it is unlikely that mixed cryoglobulinemia constitutes an independent risk factor for the progression of liver fibrosis Malignant lymphoproliferative disorders/NHL The association between infectious agents and potentially reversible “antigen driven” lymphoproliferative disorders, such as Helicobacter pylori-related gastric marginal zone B cell lymphoma has been known for many decades Recent data suggest a causative association between HCV and Non-Hodgkin Lymphoma (NHL) (Mele 2003, Duberg 2005, Giordano 2007) HCV infection leads per se to a twofold higher risk of developing NHL (Mele 2003, Duberg 2005) The most prevalent HCV-associated lymphoproliferative disorders according to the REAL/WHO classification are: follicular lymphoma, B cell chronic lymphocytic leukemia/small lymphocyte lymphoma, diffuse large B cell lymphoma and marginal zone lymphoma, including the mucosa-associated lymphoid tissue lymphoma Overall, marginal zone lymphoma appears to be the most frequently encountered low grade B cell lymphoma in HCV patients The role of HCV in the genesis of lymphoma can be either explained by the direct lymphoma-inducing effects of HCV during viral replication in normal B cells or by being a stochastic process as a result of HCV-induced proliferation of B cells (Agnello 2004) HCV-associated lymphoproliferative disorders (LPDs) are observed over the course of MC 8-10% of mixed cryoglobulinemia type II evolve into B cell NHL after long-lasting infection However, a remarkably high prevalence of B cell NHL was also found in HCV patients without mixed cryoglobulinemia (Silvestri 1997) Genetic predisposition and other factors seem to have a major impact on the development of LPDs in HCV-positive patients (Matsuo 2004) Etiology and pathogenesis of LPDs in patients with HCV infection In the development of LPDs direct and indirect pathogenic HCV-associated factors (Figure 2) are seen Sustained B cell activation and proliferation, noticed during chronic HCV infection, is an indirect pathogenic mechanism Direct pathogenic mechanisms are based on lymphotropic properties of HCV, hence on HCV’s entry into the B cells HCV RNA sequences were first detected in mononuclear peripheral blood cells (Zignego 1992) Especially CD19+ cells seem to be permissive for certain HCV quasispecies (Roque Afonso 1999) Active replication of the HCV genome in B cells is associated with activation of antiapoptotic gene BCL-2 and inhibition of p53 or c-Myc-induced apoptosis (Sakamuro 1995, Ray 1996) In this light, direct involvement of HCV in the immortalisation of B cells can be imagined (Zignego 2000, Machida 2004) 328 Hepatology 2015 Fig Pathomechanisms involved in the development of malignant lymphoproliferative disorders in patients with chronic HCV infection Indirect pathomechanism: Sustained antigen stimulation, like the binding of the viral envelope protein to the CD81 receptor, leads to excessive B cell proliferation, which in turn favors development of mixed cryoglobulinemia and/or genetic aberrations, such as t(14;18) translocation Direct pathomechanism: Viral infection of B cells, as viral replication may result in activation of proto-oncogenes (ie, BCL-2) and/or inhibition of apoptotic factors (ie, p53, c-Myc) One of the factors favoring this polyclonal B cell activation and proliferation is probably the HCV E2 protein, which binds specifically to CD81, a potent B cell activator (Cormier 2004) Treatment of lymphoproliferative disorders Because of the close correlation between the level of viral suppression and improvement of HCV-associated extrahepatic symptoms, the most effective antiviral strategy should be considered when dealing with HCV-related extrahepatic diseases New interferon-free combinations of direct acting antiviral drugs (DAA) are the standard of care for HCV infection types 1-6 Therefore these regimens can also be regarded as treatment of choice in HCV-infected patients with extrahepatic manifestations Compared to interferon-based therapies the newer DAAs have a very small number of true contraindications However drug-drug interactions due to CYP3A or P-glycoprotein metabolism, need to be taken into account and concomitant medications need to be assessed and adjusted accordingly For further information, see the other HCV chapters Mixed cryoglobulinemia While asymptomatic MC per se does not constitute an indication for treatment, symptomatic mixed cryoglobulinemia should always be treated Because asymptomatic cryoglobulinemia may evolve into symptomatic CG in the course of disease, vigilant monitoring is required and introduction of antiviral therapy in terms of prophylaxis should be considered Extrahepatic Manifestations of Chronic HCV 329 Because a causal correlation between HCV infection and mixed cryoglobulinemia has been established, the therapeutic approach of symptomatic mixed cryoglobulinemia should primarily concentrate on the eradication of the virus Indeed, clinical improvement of MC is reported in 50 to 70% of patients receiving antiviral therapy with IFN α plus RBV and mostly correlates with a drastic reduction of HCV RNA concentrations (Calleja 1999) However, cryoglobulinemic vasculitis following successful antiviral treatment persists in a small collective (Levine 2005) IFN α has been shown to be a promising therapeutic tool irrespective of virologic response Due to its antiproliferative properties on IgM-RF-producing B cells and stimulation of macrophage-mediated clearance of immunocomplexes, IFN α may lead to clinical amelioration even in virological non-responders Therefore, therapeutic success should be primarily evaluated on the basis of clinical response irrespective of virologic response In case of treatment failure of antiviral therapy and/or fulminant manifestations, contraindications or severe side effects, alternative therapeutic strategies such as cytostatic immunosuppressive therapy and/or plasmapheresis should be considered (Craxi 2008) (Figure 3, Table 4) Recent data show rituximab as an effective and safe treatment option for MC even in advanced liver disease Moreover, B cell depletion has been shown to improve cirrhotic syndrome by mechanisms that remain to be elucidated (Petrarca 2010) Systemic vasculitis In cases of severe systemic vasculitis, initial therapy with rituximab, a monoclonal chimeric antibody against CD20 B cell-specific antigen, is suggested Its efficacy and safety have been demonstrated in patients with symptomatic MC resistant to IFN α therapy, even though HCV RNA increased approximately twice the baseline levels in responders (Sansonno 2003) In light of this, combined application of rituximab with PEG-IFN α plus ribavirin in cases of severe mixed cryoglobulinemia-related vasculitis resistant to antiviral therapy seems to be the optimal therapeutic strategy, achieving amelioration of MC-related symptoms and a complete eradication of HCV in responders (Saadoun 2008) In severe rituximabrefractory mixed cryoglobulinemia-related vasculitis or acute manifestations, cycles of plasma exchange plus corticosteroids and eventually cyclophosphamide are indicated Further studies show that low dose interleukin-2 can lead to clinical improvement of vasculitis and has immunologic effects such as recovery of regulatory T cells (Saadoun 2011) Peripheral neuropathy Effectiveness of interferon-based antiviral therapy on cryoglobulinemia-induced peripheral neuropathy is still debated While HCV-related peripheral neuropathy responsive to antiviral therapy with IFN α plus ribavirin in patients with chronic HCV has been reported (Koskinas 2007), several authors report on an aggravation of cryoglobulinemic neuropathy or even de novo occurance of demyelinating polyneuropathy during IFN α and PEG-IFN α treatment (Boonyapist 2002, Khiani 2008) Therefore, application of IFN α in the presence of HCV-related neuropathy requires a cautious risk-benefit assessment However, with the approval of several interferon-free treatment options peripheral neuropathy should not be considered a contraindication for treating chronic hepatitis C 330 Hepatology 2015 Figure Therapeutic algorithm for symptomatic HCV-related mixed cryoglobulinemia (Ramos-Casals 2012) Antiviral therapy, ie, combination therapy with direct acting acting antivirals +/- RBV, is regarded as first-line therapy in cases of mild/moderate manifestations In case of contraindications, patients should be treated primarily with corticosteroids Nonresponse to antiviral therapy or drug-induced aggravation makes application of corticosteroids essential Long-term therapy with corticosteroids may result in elevation of viral load and progression of hepatic disease In light of this, rituximab represents an attractive alternative, because in this case, drug-induced viral load escalation is minor In patients with severe manifestations, treatment should focus on immunosuppression (± plasmapheresis) Due to its excellent immunosuppressive properties and relatively mild side effect profile, use of rituximab should be favored In case of good clinical response, consecutive antiviral treatment with PEGIFN α plus ribavirin may serve as maintenance therapy Therapy-refractory cases require individual treatment according to the particular center’s experience Supplementation of therapeutic strategy with antiviral therapy should be considered As eradication of Helicobacter pylori may lead to complete remission of MALT lymphoma, antiviral therapy can lead to regression of low-grade NHL in patients with HCV-related malignant lymphoproliferative disorders Combination therapy with direct acting antivirals (+/- ribavirin) should be regarded in such cases as firstline therapy (Giannelli 2003, Vallisa 2005) Remission of the hematologic disorders is closely associated with virologic response or rather achievement of sustained virologic response Effectiveness of IFN α in this context should be ascribed primarily to the drug’s antiviral properties and less to its anti-proliferative properties Extrahepatic Manifestations of Chronic HCV 331 Table Treatment of cryoglobulinemia-related disorders in patients with chronic HCV infection Author Patients Treatment Result Zuckerman N=9 Symptomatic MC non-responders to IFN α monotherapy IFN α 3x/wk + ribavirin 15 mg/kg/d CGs undetectable within weeks in 7/9 patients; clinical improvement in 9/9 within 10 weeks Sansonno N=20 Rituximab 375 mg/m / 4x/wk MC vasculitis and peripheral neuropathy resistant to IFN α montherapy Saadoun N=16 MC vasculitis in relapsers or nonresponders to IFN α/PEG-IFN α + RBV Bruchfeld 16 patients with complete clinical response; 12 sustained response throughout follow-up Viremia increases in responders Rituximab 375 mg/m / 4x/wk; PEG-IFN α 1.5 ug/kg/wk + RBV (600-1200 mg/d) for 12 months 10/16 report complete clinical response; CGs and HCV RNA undetectable in responders N=7 HCV-related renal manifestations (2/7 MC-related) IFN α + low-dose ribavirin (200-600 mg) or PEG-IFN α + low-dose ribavirin Improvement of GRF and proteinuria in 4/7 patients and sustained viral response in 5/7 Roccatello N=6 MC systematic manifestations predominantly renal (5/6) Rituximab 375 mg/m /4x/wk + rituximab 375 mg/m month and months later Decrease of cryocrit and proteinuria at months 2, 6, 12 Koskinas N=4 MC patients with severe sensory-motor polyneuropathy IFN α-2b 1.5ug/kg/wk + ribavirin 10.6 mg/kg/d for 48 weeks De Nicola N=1 Cyroglobulinemic membranoproliferative GN N=30 MC vasculitis; 23/30 non-responders to previous antiviral treatment Telaprevir + PEG-IFN + RBV Significant improvement of neurological parameters in 4/4; undetectable HCV RNA and lower CG levels in 3/4 at the end of therapy Complete resolution of acute renal failure from nephritic syndrome, undetectable HCV RNA CGs decreased from 0.45 to g/L; clinical and sustained viral response in 20/30 (66.7%) Saadoun Telaprevir (12 wks) + PEG-IFN α + RBV (48 wks) or boceprevir (44 wks) + PEG-IFN α + RBV (48 wks) Treatment of HCV-infected patients with high-grade NHL should be based on cytostatic chemotherapy HCV infection does not constitute a contraindication for cytostatic chemotherapy Unlike HBV infection, antiviral prophylaxis before chemotherapy introduction is not obligatory Chemotherapy may lead to a substantial increase in viremia Consecutive exacerbation of the infection, making discontinuation of chemotherapy mandatory, is unlikely to occur However, 332 Hepatology 2015 treatment-related liver toxicity is more frequent in HCV-positive NHL and is often associated with severe hepatic manifestations (Besson 2006, Arcaini 2009) Current data suggest that antiviral treatment may serve as maintenance therapy for achieving sustained remission of NHL after chemotherapy completion (Gianelli 2003) Further hematological manifestations HCV-associated thrombocytopenia Thrombocytopenic conditions (platelet counts below 150 x 103/uL) are often observed in patients with chronic hepatitis C and result mainly from advanced liver fibrosis and manifest cirrhosis with portal hypertension and consecutive splenomegaly (Wang 2004) Lack of hepatic-derived thrombopoietin can inter alia be recognized as an important causal factor (Afdhal 2008) As HCV RNA can be abundant in platelets (Takehara 1994) and megakaryocytes of thrombocytopenic patients, direct cytopathic involvement of HCV can be hypothesized (Bordin 1995, De Almeida 2004) Furthermore, it has been suggested that exposure to HCV may be a causative factor for the production of platelet-associated immunoglobulins, inducing thrombocytopenia through a similar immunological mechanism to that operating in immune thrombocytopenic purpura (ITP) (Aref 2009) There is a high HCV prevalence in patients with ITP (García-Suaréz 2000), and these patients exhibit diverse characteristics to HCVnegative patients with ITP, which supports the hypothesis of direct viral involvement in the development of thrombocytopenia (Rajan 2005) There is no consensus regarding the optimum treatment of HCV-related ITP Along with classical therapeutic approaches such as corticosteroids, intravenous immunoglobulins and splenectomy, antiviral therapy constitutes another option A substantial increase of platelets after application of antiviral therapy is registered in a significant percentage of patients with HCV-related ITP (Iga 2005), although evidence from further studies is required to confirm this hypothesis However, caution is recommended in thrombocytopenic patients treated with PEG-IFN α plus ribavirin, as significant aggravation of HCV-related ITP may occur on this regimen (Fattovich 1996) On the other hand, long-term use of steroids or immunosuppressive drugs is limited by an increased risk of fibrosis progression or a substantial elevation of virus, respectively A new orally active thrombopoietin receptor agonist, eltrombopag, may be used in thrombocytopenic HCV patients in the future Its efficacy has been documented in patients with HCV-related ITP (Bussel 2007) as well as in HCV-positive patients suffering from thrombocytopenia due to cirrhosis (McHutchison 2007), although, in a recent study treating patients with eltrombopag in combination with PEG-IFN α and ribavirin, portal vein thrombosis was observed in a number of patients as an unexpected complication (Afdhal 2011) FDA recently approved a new indication for eltrombopag for patients with thrombocytopenia with chronic hepatitis C to allow the initiation and maintenance of interferon-based therapy However, in countries with access to interferon-free regimens this indication may become obsolete as direct acting antivirals not aggravate thrombopenia In case of refractory disease or aggravation during the course of antiviral therapy, rituximab should be considered (Weitz 2005) Acute Liver Failure 641 Table Grade of hepatic encephalopathy (West Haven criteria) Grade Clinical findings Asterixis EEG I +/– Triphasic waves + Triphasic waves III Changes in behavior, euphoria, depression, mild confusion Inappropriate behavior, lethargy, moderate confusion Marked confusion, somnolence Triphasic waves IV Coma + – II Delta waves Prognosis With persistently high, although variable, mortality rates from ten to ninety percent, accurate prediction of the clinical course is crucial for accurate management and decision-making Most importantly, identification of the underlying etiology improves prognosis and opens the door for specific treatment The degree of hepatic encephalopathy is traditionally considered an important indicator of prognosis (O'Grady 1989) Cerebral edema and renal failure worsen the prognosis dramatically In some studies, the INR was determined as the strongest single parameter in predicting the prognosis of ALF Another interesting point is that the presence of hepatic encephalopathy means a poor prognosis for acetaminopheninduced ALF, which in contrast has little meaning for amanita mushroom poisoning LTx is the last treatment option in patients with ALF, when conservative treatment options fail and a lethal outcome is imminent Therefore, assessment of likelihood of the individual patient to undergo a fatal course is important for timely listing of the patient Standardised prognosis scores based on reproducible criteria are important in times of donor organ shortage and to avoid LTx in patients that might fully recover without LTx (Canbay 2011) King’s College criteria (KCC) was established in the 1990s based on findings from a cohort of 588 patients with ALF (O’Grady 1989) The authors also introduced a classification based on the onset of encephalopathy after an initial rise in bilirubin levels into hyperacute (6.5 and hepatic encephalapathy or INR >3.5 and any of these three: bilirubin >300 μmol/L, age >40 years, unfavorable etiology (undetermined or drug-induced) HBV Hepatic encephalopathy grade 3-4 and factor V Flying PublisheR Hepatology 2015 2015 is the year of broadening access to a range of interferon-free treatment options for hepatitis C, a multi-drug paradigm learned from drug development in the HIV arena However, this major advance is limited by substantial treatment costs in most parts of the world In other areas of hepatology, progress is less spectacular, but still remains relevant for clinical care and research Mauss, Berg, Rockstroh, Sarrazin, Wedemeyer Download the free PDF of this textbook from www.HepatologyTextbook.com Free PDF Hepatology A Clinical Textbook Mauss, Berg, Rockstroh, Sarrazin, Wedemeyer edition 2015 ... Tobaruela P, Alvarez-Mon M HCVassociated thrombocytopenia: clinical characteristics and platelet response after recombinant alpha2b-interferon therapy Br J Haematol 20 00;110:9 8-1 03 (Abstract) Garini... virus and porphyria cutanea tarda: evidence of a strong association Hepatology 19 92; 16:1 32 2-6 (Abstract) Fattovich G, Giustina G, Favarato S, Ruol A A survey of adverse events in 11 ,24 1 patients... long-term therapy with pegylated interferon -a Am J Gastroenterol 20 07;1 02: 2 72 4-3 1 (Abstract) Prummel MF, Laurberg P Interferon-alpha and autoimmune thyroid disease Thyroid 20 03;13:54 7-5 1 (Abstract)