key: cord-0919602-f2lkwfac authors: Huang, Wu‐Shiung; Chen, Rong‐Fu; Yang, Kuender D title: SIMILARITIES OF IMMUNE REACTIONS BETWEEN HEPATITIS C AND SEVERE ACUTE RESPIRATORY SYNDROME‐ASSOCIATED CORONAVIRUS INFECTIONS date: 2005-08-31 journal: J Gastroenterol Hepatol DOI: 10.1111/j.1440-1746.2005.03850.x sha: 01bcf799ad8328368eab6378d3667994fd778f16 doc_id: 919602 cord_uid: f2lkwfac nan To the Editor, Severe acute respiratory syndrome (SARS) is an emerging disease caused by a novel coronavirus (SARS-CoV). It has caused worldwide outbreaks, resulting in 8102 cases in 29 countries, with 744 fatalities in 2003. 1 SARS-CoV belongs to the Coronaviridae genus, and hepatitis C virus (HCV) belongs to the Flaviviridae genus. These are two different viruses, but both are positive single strain RNA viruses (+ssRNA), which have some similar characteristics in immune responses that might offer some insight into the treatment of SARS. Cinatl et al. first reported that interferon beta could inhibit SARS-CoV replication in in vitro culture. 2 A similar result was confirmed by Hensley et al. 3 Furthermore, other forms of interferon (interferon-alpha and -gamma) have also had an anti-SARS effect in in vitro studies. 2, 4 Loutfy et al. reported a potential benefit from the interferon alfacon-1 plus corticosteroids in SARS treatment, and found that the treatment group seemed to have reduced disease-associated impaired oxygen saturation, more rapid resolution of radiographic lung abnormalities and lower levels of creatine kinase. 5 Zhao et al. also reported that SARS patients randomly receiving interferon alpha tended to have the shortest admission days, time needed for improvement of dyspnea and time for improvement of chest X-ray films than other treatment regimens. 6 Ribavirin alone was not efficacious in in vitro anti-SARS-CoV test, or in the Zhao's randomized trial, 6 although some have suggested its clinical value. 7 Cinatl and colleagues 8 tested certain potential anti-SARS-CoV drugs including ribavirin, 6azauridine, pyrazofurin, mycophenolic acid and glycyrrhizin, and showed that glycyrrhizin has the best potency in inhibiting the replication of SARS-CoV. These results suggest that interferon alpha and glycyrrhizin could be beneficial in SARS treatment. Similarly, interferon alpha and glycyrrhizin are also effective in treating HCV infections. 9,10 Glycyrrhizin lowers serum ALT during treatment, reduces the inflammation of HCV infection, and prevents the development of hepatoma. 9,10 Glycyrrhizin has fewer side-effects and seems more effective than ribavirin in treating HCV infections. Taken together, these results suggest that SARS-CoV and HCV might have similar immunopathogenesis. Patients with chronic HCV infection tend to have Th2 dominance. 11 In a previous study, 12 we also found, as did Wang et al., 13 that a Th2 predominant cytokine profile with increases of TGFβ and IL-13 in the early stages of SARS infection (within 7 days after symptoms), followed by a Th1 predominant cytokine profile with elevation of IL-2 and IL-18 in the late stage (≥2 weeks after symptoms). This suggests that the host immune response in early SARS infection might favor viral replication, but 2-3 weeks after SARS-CoV infection, the host immune response can induce specific immunity for virus clearance or immune-mediated damage. Based on the skewed immune responses, we therefore postulate to use interferon alpha in the early stage of SARS infection to deviate Th2 predominant reaction to Th1 reaction, and hold back corticosteroids until appearance of late exacerbation showing augmented Th1 response. Another similarity between HCV and SARS-CoV infections is related to elevation of blood IL-8 levels. Polyak et al. have reported that chronic HCV infection with elevated IL-8 levels is associated with the resistance to interferon therapy. 14,15 One possible mechanism might be related to activation of p38 MAP kinase that is associated with elevated IL-8 levels and resistant interferon therapy. 16 We have recently shown that SARS infections were associated with mild elevation of IL-8 in conjunction with p38 activation in CD14 + cells. 12 How to prove the relationships between p38 activationrelated interferon resistance and SARS-CoV-or HCVrelated immune response deserves further investigation. To the Editor, We searched for antimitochondrial antibodies (AMA) in sera from women with serologically-proven Chlamydia pneumoniae infection and matched controls to indirectly confirm the recently suggested role for the bacterium in the induction of primary biliary cirrhosis (PBC). Using the most sensitive methodology for AMA determination, none of the investigated sera were found positive for AMA. The etiopathogenesis of primary biliary cirrhosis (PBC), an immune-mediated biliary disease, is still unknown. 1 Autoantibodies directed against AMA can be detected in 95% of patients with PBC and appear to be highly specific for the disease. The cloning, expression and identification of major B-cell epitopes have greatly facilitated the specific and sensitive detection of AMA. 2 It has been proposed that infectious agents or other environmental factors (bacteria, viruses or xenobiotics) might contribute to the breakdown of tolerance, leading to autoimmunity in PBC. 1 Molecular mimicry by specific exogenous proteins, which might induce crossreactive autoimmune responses to host proteins, might be involved. Interestingly, Abdulkarim et al. have recently found C. pneumoniae antigens in 25/25 (100%) of liver samples from patients with PBC but only in 8.5% of controls, thus suggesting a role for this bacterium in the pathogenesis of PBC. 3 However, these data could not be confirmed by others by using a sensitive polymerase chain reaction (PCR)-based method. 4 Based on the hypothesis that C. pneumoniae might be a major external trigger in the pathogenesis of PBC, we sought AMA in a series of women with well-defined chronic C. pneumoniae infection. They were diagnosed by both positive nested touch-down PCR on peripheral blood mononuclear cells and positive microimmunofluorescence antibody testing (IgG ≥ 1:64 or IgG > 1:64 + IgA > 1:16). 5 We note that C. pneumoniae seroprevalence in the middle-aged general population is known to be 55-60%. 5 Sera from 48 women with C. pneumoniae chronic infection (mean age ± SD: 58.3 ± 7.3) and 56 agematched healthy women (mean age ± SD: 58.7 ± 8.3) were tested for AMA. All subjects were of Italian descent and presented normal values of serum alkaline phosphatase at the time of enrollment. The latter feature was ascertained in order to attempt the identification of PBC cases at early stages. Women with C. pneumoniae infection were positive for active infection at PCR and presented titers of specific IgG, IgM, and IgA of 164 ± 231, 25 ± 39, and 5 ± 22, respectively. We sought antibodies against the three major PBCspecific mitochondrial epitopes by using ELISA with the triple-expression hybrid clone, pML-MIT-3, as previously described. 2 Briefly, the AMA-reactive immunodominant epitopes within the three distinct lipoyl domains of human pyruvate dehydrogenase complex (PDC-E2), bovine branched-chain alpha-ketoacid dehydrogenase (BCOADC-E2) and rat oxoglutarate dehydrogenase complex (OGDC-E2) were cloned and coexpressed in the plasmid vector, pGEX-4T-1 (Pharmarcia, Alameda, CA, USA), and were used as the antigen. None of the investigated sera from both the patients with C. pneumoniae infection and the controls were positive for AMA. Accordingly, by using an indirect approach to assess the role of C. pneumoniae in PBC, we were unable to support the involvement of this bacterium in the induction of the disease. A possible reason for the negative findings could be that the number of patients with C. pneumoniae studied might have been too small. We also suggest that the analysis of a large number of PBC sera with different AMA patterns for signs of C. pneumoniae infection should be pursued. However, based on the above considerations and data, we believe that the etiopathogenesis of PBC remains unknown and the search for responsible genetic or environmental factors continues. To the Editor, Ceruloplasmin plays an important role in iron transport because it is a major ferroxidase, 1 and genetic defects involving ceruloplasmin synthesis cause severe iron overload in the liver and brain. 2 The introduction of penicillamine 3 has provided significant advances in the treatment of Wilson's disease and now trientine, 4 a safer but less potent copper chelating agent, is available to patients who are intolerant to penicillamine. Penicillamine or trientine administration might reduce a patient's level of internally bioavailable copper, thereby leading to impaired iron transport. In a previous study, it was found that penicillamine further reduces serum ceruloplasmin levels and causes iron to accumulate in the liver. 5 In the present letter, we report on two male patients with Wilson's disease who were treated using trientine and phlebotomy. One of the patients developed myasthenia gravis at the age of 30 years. He was compound heterozygous for 453delC and 2871delC in the ATP7B gene, but negative for C282Y and H63D in the HFE gene. Liver histology showed chronic hepatitis with histochemical iron deposits, and his serum ferritin concentration was 277 ng/mL. Also, his serum ceruloplasmin and ferroxidase levels were low at 2 mg/dL and 240 U/ L, respectively. One month after discontinuing penicillamine treatment, trientine hydrochloride was initiated at 2500 mg/day. The other patient was a 37-year-old businessman who presented with an intentional hand tremor. The results of liver histology, where some regenerative nodules were positive for copper and/or iron grains, were suggestive of cirrhosis. He was compound heterozygous for 2332CAET and 2755CAEG in the ATP7B gene, but was free from mutations in the HFE gene. Trientine hydrochloride at 2500 mg/day reduced his serum ceruloplasmin protein from 8.9 to 5.4 mg/dL within 3 months. A liver specimen taken after 3 years of treatment was still positive for histochemical iron and his serum ferritin was 200 ng/mL and serum ceruloplasmin was 2.0 ng/mL, whereas his serum ferroxidase activity was as low as 70 U/L. Phlebotomy during trientine treatment were carried out after obtaining written informed consent from each patient where the end-point was a serum ferritin concentration of 10 ng/mL or a hemoglobin concentration of 12 g/dL. As shown in Figure 1 , postphlebotomy anemia developed in both patients when their serum ferritin levels were 38 and 17 ng/mL, respectively. Compared to patients with chronic hepatitis C, their end-points were high, suggesting their intolerance to iron removal therapy. Ferroxidase deficiency as a result of hypoceruloplasminemia might be a specific mechanism involved in iron deposition associated with impaired iron transport caused by Wilson's disease. This hypothesis is supported by the observation that iron removal by phlebotomy was insufficient for a patient with aceruloplasminemia. 2 Chelation therapy using penicillamine or trientine might result not only in the effective excretion of toxic copper, but also in the inhibition of internally bioavailable copper. When iron overload is a side-effect of using these chelaters, discontinuation of the drugs might not be recommended, but phlebotomy is enough to control iron-induced oxidative stress. 5 In future, the effects of copper chelation on iron metabolism should be studied using a larger number of patients. Upper endoscopy showed a 3 ¥ 4 cm, dark red colored, intraluminal polypoid mass which was mimicking hemangioma and stromal tumors. A biopsy could not be carried out because of the suspicion of hemangioma. Neck and thorax magnetic resonance imaging (MRI) showed an external compression to the esophagus caused by 32 ¥ 27 mm solid mass in the upper part of the thorax. The mass was extending cranially, it was well arranged with homogenous intensity with two nodules which were 37 and 36 mm in diameter. The nodules were thought to be originating from the thyroid gland and also involving the retrosternal part of the mediastenium. The nodules were causing remarkable compression to the esophageal lumen (Fig. 1a,b) . At first, the patient was thought to have esophageal hemangioma, however, because MRI images pointed to the thyroid nodules, thyroid carcinoma could not be ruled out. There was no activity on thyroid scintigraphy. Then the patient was diagnosed with thyroid carcinoma, and total thyroidectomy and segmental resection of the esophageal metastasis were carried out. Histopathological examination showed Hurthle cell carcinoma of both the thyroid nodules and the resection material of the esophagus. The patient was followed up for 5 months in outpatient clinics, he was asymptomatic with normal esophagography. Locally advanced thyroid carcinoma involving the esophagus originates from direct invasion of the tumor and is usually confined to the muscularis without extension into submucosa or mucosa layers. Patients complain of dysphagia and odynophagia resulting from direct invasion of the esophagus or extrinsic compression in association with laryngotracheal invasion. 1 The patient in the present study had dysphagia, odynophagia and hematemesis. At first, it was thought to be esophageal hemangioma because he had a left liver lobectomy as a result of a giant hemangioma and we did not attribute it to thyroid carcinoma recurrence. However, surgical resection and pathological examination showed Hurthle cell carcinoma. As with esophageal involvement of locally advanced thyroid carcinoma such as Hurthle cell carcinoma, shave resection to en bloc resection, segmental resection and esophagectomy can be carried out. If surgical treatment can not be applied because of extensive involvement, palliative dilation or stent placement might be helpful for symptomatic patients. 1 In the present patient, total thyroidectomy and segmental esophageal resection were carried out. Metastatic tumors of the upper gastrointestinal tract, especially the of the upper part of the esophagus, are relatively rare. 2, 3 If esophageal metastasis is found, neck and head tumors, malign melanoma, lung and breast cancer must be considered. [1] [2] [3] In addition to this, hepatocellular carcinoma, osteogenic sarcoma, renal cell carcinoma, germ cell tumors and prostate cancer are the other metastatic tumors to the esophagus that were published as case reports. [2] [3] [4] [5] In conclusion, metastatic cancer to the esophagus is a rare occurence. The diagnosis should be considered when patients have dysphagia and odynophagia or alarming symptoms if they have a history of previous primary cancer. Murat Akyildiz,* Omer Ozutemiz,* Fulya Gunsar,* Sinan Akay,* Ahmet Aydin,* Nevra Elmas, † Yesim Ertan, ‡ Mahir Akyildiz § and Tankut Ilter* Ege University Medical School, Departments of *Gastroenterology, † Radiology, ‡ Pathology and § General Surgery, Bornova, Izmir, Turkey Severe Acute Respiratory Syndrome (SARS)-Frequently Asked Questions about SARS Treatment of SARS with human interferons Interferon-beta 1a and SARS coronavirus replication Severe acute respiratory syndrome-related coronavirus is inhibited by interferonalpha Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study Description and clinical treatment of an early outbreak of severe acute respiratory Primary biliary cirrhosis Use of a designer triple expression hybrid clone for three different lipoyl domain for the detection of antimitochondrial autoantibodies Primary biliary cirrhosis: an infectious disease caused by Chlamydia pneumoniae? Is there a relation between Chlamydia infection and primary biliary cirrhosis? Chlamydia pneumoniae seroprevalence in immunocompetent and immunocompromised populations in Milan LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192005 Blackwell Publishing Asia Pty LtdOctober Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanism Hepatic iron overload in aceruloplasminaemia Treatment of Wilson disease with penicillamine Treatment of Wilson disease with trientine (trienthylene tetramine) dihydrochloride Iron accumulation in the liver of male patients with Wilson disease LtdOxford, UKJGHJournal of Gastroenterology and Hepatology0815-93192005 Blackwell Publishing Asia Pty LtdOctober Locally advanced differentiated thyroid cancer Direct esophageal metastasis from a distant primary tumor is a submucosal process: a review of six cases Metastatic tumors to the upper gastrointestinal tract: endoscopic experience Hepatocellular carcinoma with unusual metastasis to the esophagus Esophageal metastasis from prostate cancer: diagnostic use of reverse transcriptase-polymerase chain reaction for prostatespecific antigen