José Alexandre Sarmento

Attenuation of toll-like receptor 2-mediated innate immune response in patients with alcoholic chronic liver disease.

Background: Alcoholic chronic liver disease (ACLD) is a common form of acquired immunodeficiency.

Chronic hepatitis C treated with peginterferon alfa plus ribavirin in clinical practice

BACKGROUND/AIMS The role of genotype and viremia were retrospectively evaluated on sustained virological response (SVR) rates in routine clinical practice. METHODOLOGY From 1907 patients with chronic hepatitis C proposed for treatment, we analysed 1380 (1124 naive and 256 treatment-experienced) with complete follow-up. Genotype and HCV RNA quantification were assayed by commercial tests. Viremia was considered high if >800,000IU/mL, and low if <400,000IU/mL. Liver fibrosis was staged in 614 patients. RESULTS Genotype 1 was the most frequent (60%), followed by 3 (25%), 4 (9%) and 2 (2%); 3.2% had other or unclassified genotype. Genotype 1 was more prevalent in central Portugal and genotype 4 in the south. Viremia was =800,000IU/mL in 54.6% and <400,000IU/mL in 34.6% of the patients, particularly in genotype 2 (p<0.03) and 4 (p<0.001). Genotype non-1 had a significantly lower viral load (p=0.004). Mild or moderate fibrosis was present in 71.7% and bridging fibrosis or cirrhosis in 28.3%, with no differences among genotypes. Treatment was discontinued in 19.8%. SVR was achieved in 55.3% of naive and 36.3% of re-treated patients. CONCLUSIONS Standard treatment of chronic hepatitis C in real-life achieves similar results obtained in clinical trials, despite differences of demographic and viral parameters.

Hepatobiliary and Pancreatic: Terry's nails and liver disease

In 1954, Dr R Terry, writing in The Lancet, described a nail abnormality characterized by a white nail bed with a distal band, 1–2 mm in length, that had a normal pink color. Associations were noted with a variety of disorders including chronic liver disease. Subsequent studies confirmed an association with cirrhosis but also showed associations with congestive cardiac failure, diabetes mellitus and advanced age. There was no apparent relationship to anemia or hypoalbuminemia. Histological studies of the nail bed have shown vascular changes (telangiectasias) in the proximal and distal bands but reasons for the color variations remain unclear. One possibility is that the proximal and distal nail bed have separate blood supplies. The disorder needs to be distinguished from leukonychia (white nails) that appear to be related to minor injuries to the nail during growth. In contrast to Terry’s nails, patchy leukonychia is lost as the nail grows distally. A middle-aged male was referred to our hospital in 1997 because of minor changes in liver enzymes. He was noted to have unusual fingernails (Figure 1) and toenails (Figure 2). Apparently, these changes had been present since the age of 6 years. The proximal nail bed was white, the lunula was absent and the distal nail had a normal pink color. The features were typical of Terry’s nails. He was positive for HBsAg and antiHBe with HBV DNA levels >10 copies/ml. His serum albumin was within the reference range and he was negative for other hepatitis viruses. A liver biopsy showed mild liver inflammation without fibrosis. He was initially treated with lamivudine and subsequently with the combination of lamivudine and adefovir. Currently, he has normal liver function tests with undetectable levels of HBV DNA. A Fibroscan value was within the reference range. Terry’s nails would appear to be an uncommon feature of hepatitis B and is rare in patients without cirrhosis such as the patient described above. In patients with Terry’s fingernails, 50% of patients show similar changes in all nails but some have normal and abnormal nails, apparently in a random fashion. The frequency of the association between Terry’s fingernails and Terry’s toenails remains unclear.

Rectal ischaemia after stapled hemorrhoidopexy causing pain or bleeding: report of three cases.

Stapled hemorrhoidopexy (SH), unlike traditional approaches, does not remove haemorrhoidal tissue. Instead, it interrupts the haemorrhoidal circulation and elevates rectal mucosa. Conventional surgical haemorrhoidectomy seems to be more effective in the long term; however, in the short term, it is associated with higher postoperative morbidity, perianal complaints and longer periods of hospitalisation and recovery [1]. In the literature, there are only a few studies examining long-term results after haemorrhoidopexy or comparing SH with haemorrhoidectomy [2, 3]. Postoperative bleeding occurs in 1–4 % of the cases, and there is no effective way to prevent this; reintervention with haemostatic sutures is required [4]. Postoperative pain, specially associated with defecation, although less severe and of shorter duration than postoperative pain after conventional haemorrhoidectomy, is the most common complaint and is caused by thrombosis of the haemorrhoidal tissue, sutures too near of the dentate line or a small abscess/area of inflammation around the suture [5]. We report 3 patients with complications after SH which, to the best of our knowledge, have not yet been described. Two previously healthy patients complained of severe anal pain 3 days after SH, accompanied by tenesmus. At sigmoidoscopy, ischaemia was apparent immediately below the suture line, extending to the anal canal, without involvement of the latter. In both cases, the suture line and upstream rectum appeared normal on endoscopy (Fig. 1). One of the patients had sphincter hypertonicity at digital rectal examination. Conservative treatment was started with non-steroidal anti-inflammatory drugs (NSAIDs), diltiazem ointment and mesalamine suppositories with resolution of symptoms in 5 days in one of the patients. The second patient’s complaints persisted for 3 weeks with gradual improvement in symptoms after injection of botulinum toxin. Meanwhile, pelvic magnetic resonance imaging was performed and, no changes were seen. The third patient had no short-term complications other than urinary. However, 6 days after the procedure, he was admitted in the emergency room due to severe rectal bleeding. At physical examination, he was hypotensive and pale and there was blood on the glove at digital rectal examination. There was a 6-unit drop in haemoglobin (15.3 g/dL ? 9.1 g/dL). He underwent reoperation, and a supplementary haemostatic suture was placed in an area of necrosis with active bleeding. A sigmoidoscopy performed 2 days later revealed an area of ischaemia, occupying onethird of the lower rectal circumference, and 2–3 cm in length, with evidence of ulceration and congestion (Fig. 2). The suture line and upstream rectum had a normal endoscopic appearance, and there was no involvement of the anal canal. Postoperative bleeding is technically difficult to deal with. Staple line bleeding points needing haemostasis at the time of surgery have been reported since the original description of SH, and reintervention may be necessary. In these cases, bleeding is usually from arteriolar vessels of the submucosa, which could be stopped by local haemostasis. It could also be due to staples not achieving proper haemostasis or folded mucosa in the staple line. In our patients, it may have been not only from sloughing of the scar, but also due to postoperative ischaemia of the distal rectum, causing mucosal and submucosal ulceration with exposure of vessels. A pre-existing local vascular defect E. Rodrigues-Pinto (&) J. A. Sarmento F. Azevedo G. Macedo Gastroenterology Department, Centro Hospitalar São João, Porto. Al. Prof. Hernâni Monteiro, 4200-319 Porto, Portugal e-mail: edu.gil.pinto@gmail.com

Anal cytology, histopathology and anoscopy in an anal dysplasia screening program: is anal cytology enough?

BACKGROUND AND AIM The human papilloma virus is the leading cause of anal squamous cell carcinoma. Cytological screening may reduce the associated morbidity and mortality. The aim of the study was to estimate the agreement between anal cytological examination, histopathology and anoscopic visual impression. METHODS A prospective study of patients who underwent anal dysplasia screening between 2011 and 2015, in a proctology clinic of a tertiary referral center. RESULTS During the study period, 141 patients (91% men, 87% with HIV infection) underwent 175 anal cytology tests. Of these, 33% were negative for intraepithelial lesions or malignancy (NILM), 22% were atypical squamous cells of uncertain significance (ASCUS), 33% were low-grade squamous intraepithelial lesion (LSIL) and 12% were high-grade squamous intraepithelial lesion (HSIL). With regard to anoscopic visual impression, 46% of patients had no lesions and excision/biopsy of the identified lesions was performed in the remaining patients. The weighted kappa-agreement between abnormal cytological results and anoscopic visual impression was moderate (k = 0.48). The weighted kappa-agreement between simultaneous anal cytological examinations and anal histopathologic findings was low (kappa = 0.20). With regard to the histological examination of cases with HSIL or superficially invasive squamous cell carcinoma, 64% of patients had dysplasia of a lower grade according to the cytological analysis (6 ASCUS, 18 LSIL and 4 NILM). CONCLUSION There was a poor correlation between anal cytology, histopathology and anoscopic visual impression and a high number of histological studies of HGD that were of a lower dysplastic degree according to the cytological examination. Therefore, anal cytology screening should not be used as the sole method of anal dysplasia screening.

Non-healing perianal ulcer in an immunocompetent patient as the presenting sign of a systemic disease

Dear Editor: Tuberculosis (TB) is still a major health problem worldwide. In Western countries, the incidence of pulmonary TB has decreased, and extrapulmonary tuberculosis has become very rare with the introduction of effective antituberculous chemotherapy. Extra pulmonary TB accounts for less than 15 % of all cases, while the gastrointestinal location constitutes less than 1 % of extrapulmonary forms of the disease. We report the case of a 39-year-old man with an unremarkable past medical history that presented to the emergency department complaining about perianal itching and pain. On physical examination he had an infiltrative ulcer at the right perianal region that was treated with antifungals, antibiotics, and antihistamines without significant relief. Four months later, the patient started complaining about diarrhea and abdominal pain in addition to the perianal symptoms. He also reported anorexia and weight loss (5 Kg in the last 2 months), without other associated symptoms. On physical examination, he was pale, had a painful abdomen without any tenderness on palpation, and maintained the perianal ulcer previously described. Laboratory tests were remarkable for microcytic anemia, hypoalbuminemia, and elevated C-reactive protein and sedimentation rate. Abdominal ultrasound showed a diffuse wall thickening of distal ileum and cecum. The patient was admitted to the hospital, and a biopsy of the perianal ulcer was performed. Histological examination of perianal ulcer showed epithelioid granulomas with caseous necrosis and Langhans’ type multinucleated giant cells. Ziehl–Neelsen (Z-N) staining was positive for acid-fast bacilli. A thoracic computed tomography (CT) scan was performed and revealed multiple micronodules, tree-in-bud opacities, and peribronchial nodules with cavitation predominantly on upper lobes. The abdomino-pelvic CT scan revealed several areas of intestinal wall thickening in the proximal and distal ileum and cecum and multiple enlarged lymph nodes in the mesentery root. A colonoscopy was also performed and showed ulceration of cecum and ulceration and stenosis of ileocecal valve preventing ileal intubation. The histological examination confirmed intestinal involvement by a granulomatous chronic inflammatory process with acid-fast bacilli on Z-N staining polymerase chain reaction (PCR), and culture analysis confirmed the diagnosis of perianal, intestinal, and pulmonary tuberculosis. HIV serologies were negative. Patient was started on antituberculous (anti-TB) treatment with isoniazid, rifampicin, ethambutol, and pyrazinamide, and after 6 weeks of treatment the perianal ulcer was completely healed. Although, the patient had to be admitted to the hospital due to subocclusive symptoms in the context of intestinal tuberculosis that were treated with steroids in addition to anti-TB treatment. Now, the patient is on the eleventh month of treatment (he will complete 1 year), healthy and asymptomatic. Perianal ulcer did not recur, and PCR/cultural analysis of sputum and intestinal samples are already negative. TB is still a major health problem worldwide. Indeed, there are nine million cases of active tuberculosis being reported annually, and one third of the world’s population is supposed * Patrícia Andrade anapatriciarandrade@gmail.com

703 Multidrug-Resistant Chronic Hepatitis B -Impact on Therapy Outcome

BACKGROUND: The occurrence of Hepatitis B virus (HBV) polymerase mutations was a major limitation of chronic hepatitis B (CHB) treatment until the introduction of entecavir (ETV) and tenofovir (TDF). Cross-resistance to ETV is well documented in the presence lamivudine (LAM) resistance mutations and ETV specific mutations. To date, no mutations that confer resistance to TDF have been described, nevertheless adefovir (ADF)-associated resistance mutation N236T proved to confer low-level resistance to TDF in studies in vitro. METHODS AND AIMS: Retrospective analysis of HBV monoinfected patients treated with TDF or ETV that performed viral mutations testing (mostly INNO-LiPA hybridization assays, Innogenetics, Belgium) in a single center. Evaluation of the efficacy of antiviral therapy in the presence of multidrug-resistantmutants (MDR). RESULTS: In a group of 181CHBpatients treated with TDF or ETV (5% combination TDF+ETV), 89 (49%) had HBV polymerase gene mutation analysis. Sixty-eight patients (76% of tested) presented several mutations including N236T and 8% had only nucleoside resistant strains. MDR were detected in 9% of naive patients and 49.5% of previously treated patients. Fifty-three (78%) of the MDRHBV patients were treated with TDF and 15 (22%) were taking ETV. MDR were more frequent in HBeAg positive hepatitis (p 250 IU/mL at the beginning of therapy (p=0.002) and baseline HBV viral load >100000 IU/mL (p=0.008) were predictive of MDR presence. During therapy, patients without MDR achieved more HBeAg negativation (p=0.007), anti-HBe seroconversion (p=0.019) and more frequently achieved HBV DNA suppression (p=0.003). Globally, mean treatment duration until HBV DNA undetectability was 24.8 months with MDR versus 8.2 months without (p<0.001). In MDR CHB patients, treatment with TDF was associated with greater HBV DNA supression than ETV (p<0.001), and shorter time to undetectability (18.9 versus 45.2 months, p=0.001). In multivariate analysis, baseline MDR (p<0.001), HbeAg positive (p<0.001) and viremia (p=0.043) were independently associated with longer time to HBV DNA undetectability. CONCLUSIONS: Multidrug-resistant CHB was detected in 9% of naive patients and in half of those previously treated. Its occurrence was associated with more difficult to treat CHB and slower treatment response. TDF was more effective than ETV in MDR HBV patients. This impact in antiviral therapy could have implications in CHB management, particularly in severe cases with decompensated cirrhosis and/or indication for liver transplantation.

Gastrointestinal: Anal Buschke Loewenstein tumor

A 33 year-old male was diagnosed with Human immunodeficiency virus (HIV) infection in 2009, CD4 count of <200 cells/mL and HIV RNA 756000 cps/ml. Antiretroviral therapy (ART) was started. In 2010, a mass involving the rectum and bladder was diagnosed as a pelvic non-Hodgkin′s lymphoma (diffuse large B-cell lymphoma) and initially submitted to six cycles of chemotherapy—CHOP (Cyclophosphamide, doxorubicin, vincristine and prednisolone) and followed by radiotherapy (45 Gy), due to the persistence of the pelvic lesion. Six months later, a painful and progressively larger perianal lesion appeared complicating evacuation. A 15 cm ¥ 10 cm exophytic mass of the perianal region was observed (Figures 1 and 2). Laboratory tests showed normal hemoglobin level (15 g/dl), white blood cells count (4.68 ¥ 10/L), platelets (232 ¥ 10/L), CD4 count >200 cells/mL, and HIV RNA not detected. Endoscopic ultrasound (EUS) revealed an external anal sphincter defect. This HIV patient had a large, vegetative, cauliflower-like tumor in the perianal region, with local invasion revealed by EUS and histology confirming a condyloma acuminata (Figure 3). Anal Buschke Loewenstein Tumor (Giant Condyloma Acuminata) was diagnosed. This is a rare disease with a potentially fatal course, due to human papillomavirus (HPV) infection, most commonly HPV types 6 and 11 and occasionally types 16 and 18. It is characterized by its size, capability of local infiltration, and high recurrence rate. There seems to be a trend towards younger age at presentation and male predominance. Perianal mass, pain, abscess, fistula and bleeding are the most common presenting symptoms. It most often affects the glans penis, but has also been reported in the scrotum, vulva, perianal region, and bladder. Local invasion and local recurrence are the major sources of morbidity in this disease. Despite the benign histological pattern in most cases, transformations into verrucous carcinoma and squamous-cell carcinoma have been described. Wide surgical excision, radiochemotherapy, topical and intralesional chemotherapy, carbon dioxide laser therapy, and photodynamic therapy have been used as treatment. Wide local excision remains the mainstay of therapy. The high recurrence rate after wide local excision has prompted the employment of therapy adjuncts. Both radiation and chemotherapy have been used as the most common preoperative regimen. This patient refused surgery and abandoned follow up.