Nonalcoholic steatohepatitis in morbid obese patients: coffee consumption vs. disease severity.

INTRODUCTION: Obesity correlates with nonalcoholic fatty liver disease (NAFLD) and occurs in 90 to 100% of severely obese individuals (body mass index [BMI] > 35 kg/m2). Coffee consumption (CC) has been associated with reduced progression of fibrosis in both hepatitis C infection and NAFLD; however, this topic is still under discussion when this liver disease affects severely obese individuals. OBJECTIVE: To assess the association between CC, insulin resistance (IR) and histological NAFLD morbid obese patients. MATERIAL AND METHODS: Cross-sectional study, including obese individuals undergoing bariatric surgery, liver biopsy and histological diagnosis between September 2013 and August 2014. The patients were classified into 3 groups according to their weekly CC: 0- 239.9 mL; 240-2099.9 mL and ≥ 2100 mL. RESULTS: A total of 112 obese individuals were included (BMI = 41.9 ± 4.3 kg/m2), with a mean age of 34.7 ± 7.4 years; 68.6% were women. CC was reported by 72.3% of patients. There were no statistical significant differences between groups regarding the presence of IR (84.8% vs. 74.2% vs. 75.9%; p = 0.536). Progressively higher percentages of individuals with normal liver histology were observed (14.7% vs. 21.9% vs. 24.3%). NASH (65.7% vs. 70.3% vs. 57.5%) were observed among those who consumed greater coffee volumes (p = 0.812). In conclusion, obese individuals with elevated CC exhibited lower frequencies of NASH, although with no statistical significance in this sample.

MAP Kinase Pathways: Molecular Roads to Primary Acral Lentiginous Melanoma.

The etiology and pathogenesis of lentiginous acral melanomas are poorly understood. Recent studies have postulated that DNA repair mechanisms and cell growth pathways are involved in the development of melanoma, particularly changes in the MAPK pathways (RAS, BRAF, MEK 1/2, and ERK 1/2). The aim of this study is to assess the status of the MAP kinase pathways in the pathogenesis of acral melanomas. The authors examined the components of the RAS-RAF-MEK-ERK cascades by immunohistochemistry in a series of 16 primary acral melanomas by tissue microarray. The expression of MAP kinase cascade proteins changed in most cases. The authors observed that 57.14% of cases were BRAF positive and that 61.53%, 71.42%, and 71.42% of cases were positive for MEK2, ERK1, and ERK2, respectively; RAS was not expressed in 92.31%, and all cases were negative for MEK1. The absence of RAS and positivity for MEK2, ERK1, and ERK2 were most seen in invasive cases with high thickness. These aspects of the MAPK pathway require further examination in acral melanomas between different populations. Nevertheless, the results highlight significant alterations in the MAP kinase cascades that are related to histological indicators of prognosis in primary acral melanomas.

A case of conventional treatment failure in visceral leishmaniasis: leukocyte distribution and cytokine expression in splenic compartments.

BACKGROUND: In this paper we study the distribution of leukocyte populations and of cytokine-producing cells in the spleen of a patient with visceral leishmaniasis resistant to clinical treatment. It is the first attempt to compare the distribution of leukocyte populations and cytokine-producing cells in the splenic compartments of a patient with visceral leishmaniasis with those observed in patients without the disease. CASE PRESENTATION: A 25-year-old male, farmer, was hospitalized on several occasions with diagnosis of visceral leishmaniasis and received all recommended treatments for the disease with only transient improvement followed by relapse. He was eventually subjected to splenectomy in order to control the effects of hypersplenism and to potentially overcome infection. After surgery and combined chemotherapy, the disease evolved to cure. In comparison with the spleens of the other two patients without visceral leishmaniasis, an increase was observed in the CD4/CD8 ratio and in the number of IL-10- and FoxP3-producing cells, while the number of IL-17-producing cells was lower in the spleen of the patient with visceral leishmaniasis. CONCLUSION: This report confirms previous data on changes in the CD4/CD8 ratio in the spleens of patients with visceral leishmaniasis. Additionally the data presented herein suggests that splenic FoxP3- and IL-17-producing cells are involved in the chronicity of visceral leishmaniasis.

An integrated analysis of the structural changes and gene expression of spleen in human visceral leishmaniasis with and without HIV coinfection.

The spleen plays a pivotal role in the pathogenesis of visceral leishmaniasis. In severe forms of the disease, the spleen undergoes changes that can compromise its function in surveilling blood-circulating pathogens. In this study, we present an integrated analysis of the structural and gene expression alterations in the spleens of three patients with relapsing visceral leishmaniasis, two of whom were coinfected with HIV. Our findings reveal that the IL6 signaling pathway plays a significant role in the disorganization of the white pulp, while BCL10 and ICOSLG are associated with spleen organization. Patients coinfected with HIV and visceral leishmaniasis exhibited lower splenic CD4+ cell density and reduced expression of genes such as IL15. These effects may contribute to a compromised immune response against L. infantum in coinfected individuals, further impacting the structural organization of the spleen.

Obliterative portal venopathy: A neglected and probably misdiagnosed disease with peculiar etiology in South America.

Background and Aim: Obliterative portal venopathy (OPV) is one of the causes of non-cirrhotic portal hypertension. However, many aspects of OPV remain unclear, including the etiology, pathogenesis, and natural history. The aim of this study was to describe the clinical features of OPV in a series of patients in Brazil in whom OPV was diagnosed through liver biopsy. Methods: Forty-three consecutive adult patients with OPV were retrospectively selected as a case series based on histologic criteria, defined by the presence of at least portal fibrosis, phlebosclerosis, disappearance and/or reduction of the caliber of portal vein branches, and exclusion of cirrhosis. Clinical and laboratory data were analyzed. Clinically significant portal hypertension was considered in the presence of esophageal varices and/or ascites. Results: The mean age of patients at diagnosis was 44.5 ± 11 years, who were predominantly female (81%). Clinically significant portal hypertension was found in 28% of cases. The most frequent indication for liver biopsy was the elevation of liver enzymes, mostly γ-glutamyl transferase (GGT) in 76% of patients, averaging 222 IU/L (upper limit of normality up to 40 IU/L) and alanine aminotransferase (ALT) in 64%, mean 84 IU/L (38 IU/L). One-third of our patients had exposure to medications, especially herbal medicines, at the time of enzymatic changes. Other risk factors highlighted were features of autoimmunity in 25% of patients or thrombophilia in 20%. Conclusion: OPV can be diagnosed even before the onset of portal hypertension, ALT elevation, and especially GGT elevation in most cases. Its etiology is not defined, but autoimmune diseases, thrombophilia, and the use of medications or herbal medicines may play a role.

Epidemiological assessment of liver disease in northeastern Brazil by means of a standardized liver biopsy protocol.

BACKGROUND/AIM: The main objective of this study was to describe the profile of patients who were benefitted in a collective effort to perform liver biopsies in Bahia, Brazil. METHOD: A cross-sectional study was conducted with a sample composed of all the patients who were submitted to liver biopsy during a collective effort carried out in Bahia between July 2007 and November 2009. At the time of the procedure, date on the age and gender of patients and the reason for performing the biopsy were recorded. Data on the degree of fibrosis and the presence of co-morbidities. Following statistical analysis, the frequency of the liver diseases that led to the biopsy procedure was described, and the profile of the patients was stratified into groups according to the most prevalent etiologies. RESULTS: Of the 550 patients evaluated, 55.3% were men and 44.7% women. Mean age was 46.63 ± 11.59 years and there was no statistically significant difference in age between males and females. Of the 550 patients, 72% had hepatitis C and the mean age of these patients was 48.49 ± 10.1 years, significantly higher than the mean age of the patients with hepatitis B (40.41 ± 12.43 years). Furthermore, 70.7% of the patients with hepatitis C were between 41 and 60 years of age. The most frequent fibrosis grade was F2 (44%) and the prevalence of advanced fibrosis was 27.7%. Overall, 85 patients, most of them men, had some degree of iron overload. With respect to the safety of the biopsy procedure, severe complications occurred in only two patients. CONCLUSION: Hepatitis C is the predominant liver disease that demanded liver biopsy. The profile of the patients who benefitted from this collective effort is similar to that of patients in the rest of the country. Moreover, non-Ultrasonography guided liver biopsy is safe and the collective effort to carry out liver biopsies in Bahia was found to be a viable venture.

Immune and inflammatory responses to Leishmania amazonensis isolated from different clinical forms of human leishmaniasis in CBA mice.

Leishmania amazonensis causes different diseases depending on the host and parasitic virulence factors. In this study, CBA mice were infected with L. amazonensis isolates from patients with localized (Ba125), diffuse cutaneous (Ba276) or visceral leishmaniasis (Ba109). Mice infected with Ba125 and Ba276 progressed rapidly and lesions displayed an infiltrate rich in parasitized macrophages and were necrotic and ulcerated. Ba109 induced smaller lesions and a mixed inflammatory infiltrate without necrosis or ulceration. Ba109 induced an insidious disease with lower parasite load in CBA mice, similar to human disease. Levels of IFN-γ, IL-4 and IL-10 did not differ among the groups. Because all groups were unable to control the infection, expression of IL-4 associated with low production of IFN-γ in the early phase of infection may account for susceptibility, but others factors may contribute to the differences observed in inflammatory responses and infection progression. Evaluation of some parasitic virulence factors revealed that Ba276 exhibits higher ecto-ADPase and 5'-nucleotidase activities compared to the Ba109 and Ba125 strains. Both Ba276 and Ba125 had higher arginase activity in comparison to Ba109. Finally, these data suggest that the differences in enzyme activities among parasites can account for differences in host inflammatory responses and infection progression.

Assessment of histological liver alterations in dogs naturally infected with Leishmania infantum.

BACKGROUND: The liver plays a central role in the development of canine visceral leishmaniasis. Studies of natural infection in animals and humans indicate a direct relationship between resolution of infection and the formation and maturation of granulomas in the liver. However, in contrast to other reports in the literature, the present study found no differences in the characteristics of hepatic granulomas that could be related to resistance or susceptibility to Leishmania. Here, we describe the hepatic alterations observed in dogs with differing clinical manifestations of visceral leishmaniasis in an endemic area in the state of Bahia, Brazil. METHODS: We examined 148 animals in an endemic area. The animals were clinically examined, and the infection was determined by ELISA, spleen aspirate culture and quantitative PCR. The animals were grouped into asymptomatic or symptomatic based on the number of signs of LV. The histological liver evaluation was performed in a blinded way. RESULTS: Our results indicated no association between the characteristics of granulomas and clinical presentation. We found an association between the intensity of this inflammatory response and parasite load in the animals' spleens. It is important to note that while hepatic alterations, such as portal and perivascular inflammation and the presence of larger amounts of granulomas, were linked with higher parasite loads, we found the inverse to be true with respect to intrasinusoidal lymphocytosis, the formation of intrasinusoidal inflammatory cell aggregates and Kupffer cell hypertrophy. CONCLUSIONS: Our findings suggest that the presence of mononuclear inflammatory cells inside the sinusoids is more important than that of organized granulomas in terms of the containment of parasitism by the host. We suggest that the presence of granulomas indicates the failure of a first line of defense mechanism in the control of parasite infection, which could be related to the presence of inflammatory cells and Kupffer cell hypertrophy inside the sinusoids. We further demonstrated that dogs with active Leishmania spp. infection present a higher frequency of inflammatory changes in the liver. In addition to being correlated with the severity of clinical manifestation, these hepatic alterations were also associated with changes in hematological and biochemical parameters.

Concomitant early mucosal and cutaneous leishmaniasis in Brazil.

Mucosal leishmaniasis (ML) is often clinically silent until reaching a highly advanced state. In this prospective study, 6 of 220 patients with early cutaneous leishmaniasis were diagnosed with mucosal involvement by otorhinolaryngological examination (a rate similar to the reported rate of late ML). Detection of early ML may represent an important strategy in preventing severe mucosal destruction in human leishmaniasis.

Heat therapy for cutaneous leishmaniasis elicits a systemic cytokine response similar to that of antimonial (Glucantime) therapy.

Controlled heat delivered as radio waves has been used successfully in the treatment of cutaneous leishmaniasis (CL). Here we investigated whether local heat therapy has systemic effects, as measured by the modulation of cytokine production following heat therapy of CL lesions compared with antimonial (Glucantime) treatment. Patients with CL were randomly assigned into this study. Heat (50 degrees C for 30s) was applied once. The control group received Glucantime therapy for 20 d. Cytokine production by peripheral blood mononuclear cells was assayed on days 0, 14 and 28 after onset of treatment. At the end of 28 d, 75% of lesions were healing or healed in the heat therapy group and 90% in the control group (P=0.1261). There was a decrease in IFN-gamma, IL-5 and TNF-alpha levels comparing day 0 with day 28 in both groups, but no difference between the two therapy groups. In patients with only one of several lesions treated with heat therapy, the untreated lesions also healed. Local heat therapy in CL lesions leads to systemic cytokine responses similar to that induced by systemic Glucantime therapy.

Non-alcoholic fatty liver disease and insulin resistance: importance of risk factors and histological spectrum.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) has been associated with several metabolic conditions (MC) and secondary causes, but the relationship between insulin resistance (IR) and the underlying aetiology of NAFLD has not been extensively explored. OBJECTIVE: To determine the frequency of IR among NAFLD patients and to describe IR according to risk factors and histological findings of the disease. METHODOLOGY: A case-series study of 64 patients with clinical and histological diagnosis of NAFLD. IR was calculated by homeostasis model assessment (HOMA) and IR was considered when HOMA > or = 3. Histological grades of NAFLD were: stage 1, steatosis isolated; stage 2, steatosis and inflammation; stage 3, steatosis and ballooning degeneration; stage 4, steatosis and fibrosis and/or Mallory bodies. Fibrosis was graded 0-4 (cirrhosis). RESULTS: IR was found in 21 (33%) patients. Among those with IR, 16 patients (76%) had associated MC and five patients (24%) had exposure to petrochemicals. The mean value of HOMA varied from 3.5 in NAFLD associated with MC to 1.6 in patients with exposure to petrochemicals (P < 0.03). Waist circumference was the metabolic factor most strongly associated with IR (P < 0.005). Steatohepatitis (NASH) was observed in 54 (84.3%) cases. The HOMA mean value was significantly higher in patients with advanced fibrosis. CONCLUSIONS: IR occurred in 33% of the NAFLD patients, being more frequent among those with MC than among those with exposure to petrochemicals. The presence of IR in cases with advanced fibrosis suggests that it may influence the prognosis of NAFLD.

Liver histological alterations in patients with chronic hepatitis C and normal ALT levels in the city of Salvador, Northeast-Brazil.

UNLABELLED: Patients with chronic hepatitis C can have variable clinical progression. Hepatic histological alterations appear to be milder in asymptomatic subjects who have persistently normal ALT levels. AIMS: To evaluate the severity of histological liver alterations in blood donors with normal and elevated ALT levels. METHODS: We evaluated volunteer blood donors from the main blood bank of the city of Salvador-Brazil. Those who were anti-HCV positive were invited to participate in the study. Serum ALT and AST levels were measured at two time points, two months apart. Donors were divided into two groups: group I, individuals with ALT > 1.5 times the upper limit of normal in at least one time point and group II, individuals with normal or near normal ALT, at both time points RESULTS: We evaluated 30,232 blood donors and 528 (1.7%) of them were anti-HCV positive. Eighty-two attended our service and HCV infection was confirmed in 66 individuals. Male gender predominated in both groups; the mean age was 36 for group I, and 33 for group II. Tattoos and intravenous illicit drug use were frequently-encountered risk factors. Liver biopsy was done in 43 subjects. Among donors with elevated ALT, two (10%) had minimum alterations, while in group II normal liver or minimum alterations were observed in six (26%) subjects. Chronic hepatitis or cirrhosis was encountered in 35 (81%) individuals: three (15%) and five (21%) subjects had chronic hepatitis without inflammatory activity, 10 (50%) and 11 (48%) had minimum to moderate activity and five (25%) and one (4.3%) had cirrhosis, in groups I and II, respectively (P was not significant). CONCLUSIONS: The prevalence of anti-HCV among this population of volunteer blood donors was 1.7%, and these subjects had few liver histological alterations or chronic hepatitis and cirrhosis. Liver injury severity was significant in patients with elevated ALT, however subjects with normal levels may also present chronic hepatitis and cirrhosis.

Extracellular vesicles from Leishmania-infected macrophages confer an anti-infection cytokine-production profile to naïve macrophages.

BACKGROUND: Extracellular vesicles (EVs) are structures with phospholipid bilayer membranes and 100-1000 nm diameters. These vesicles are released from cells upon activation of surface receptors and/or apoptosis. The production of EVs by dendritic cells, mast cells, macrophages, and B and T lymphocytes has been extensively reported in the literature. EVs may express MHC class II and other membrane surface molecules and carry antigens. The aim of this study was to investigate the role of EVs from Leishmania-infected macrophages as immune modulatory particles. METHODOLOGY/PRINCIPAL FINDINGS: In this work it was shown that BALB/c mouse bone marrow-derived macrophages, either infected in vitro with Leishmania amazonensis or left uninfected, release comparable amounts of 50-300 nm-diameter extracellular vesicles (EVs). The EVs were characterized by flow cytometry and electron microscopy. The incubation of naïve macrophages with these EVs for 48 hours led to a statistically significant increase in the production of the cytokines IL-12, IL-1ß, and TNF-α. CONCLUSIONS/SIGNIFICANCE: EVs derived from macrophages infected with L. amazonensis induce other macrophages, which in vivo could be bystander cells, to produce the proinflammatory cytokines IL-12, IL-1ß and TNF-α. This could contribute both to modulate the immune system in favor of a Th1 immune response and to the elimination of the Leishmania, leading, therefore, to the control the infection.

Severe clinical presentation of visceral leishmaniasis in naturally infected dogs with disruption of the splenic white pulp.

In this work, we investigated the association between the disruption of splenic lymphoid tissue and the severity of visceral leishmaniasis in dogs. Clinical and laboratory data from 206 dogs were reviewed. Spleen sections collected during the euthanasia of these animals were analyzed, and the splenic lymphoid tissue samples were classified as well organized (spleen type 1), slightly disorganized (spleen type 2), or moderately to extensively disorganized (spleen type 3). Of 199 dogs with evidence of Leishmania infection, 54 (27%) had spleen type 1, 99 (50%) had spleen type 2, and 46 (23%) had spleen type 3. The number of clinical signs associated with visceral leishmaniasis was significantly higher in the animals with evidence of Leishmania infection and spleen type 2 or 3 than in the animals with spleen type 1. Alopecia, anemia, dehydration, dermatitis, lymphadenopathy, and onychogryphosis were all more frequent among animals with evidence of Leishmania infection and spleen type 3 than among the dogs with evidence of Leishmania infection and spleen type 1. The association between the severity of canine visceral leishmaniasis and the disorganization of the splenic lymphoid tissue was even more evident in the group of animals with positive spleen culture. Conjunctivitis and ulceration were also more common in the animals with spleen type 3 than in the animals with spleen type 1. The serum levels (median, interquartile range) of albumin (1.8, 1.4-2.3 g/dL) and creatinine (0.7, 0.4-0.8 mg/dL) were significantly lower and the serum levels of aspartate aminotransferase were significantly higher (57, 39-95 U) in animals with spleen type 3 than in animals with spleen type 1 (2.8, 2.4-3.4 g/dL; 0.9, 0.7-1.2 mg/dL and 23, 20-32 U, respectively). Our data confirm the hypothesis that disruption of the splenic lymphoid tissue is associated with a more severe clinical presentation of canine visceral leishmaniasis.

Anti-Golgi complex antibodies during pegylated-interferon therapy for hepatitis C.

BACKGROUND/AIM: Pegylated interferon (Peg-IFN) plus ribavirin is the standard therapy for hepatitis C. Peg-IFN has several antiviral mechanisms, but its role in hepatitis C treatment seems to be related to its immunomodulatory effect. Ribavirin, an antiviral agent, potentiates IFN activity when added to it. Both drugs are associated with adverse reactions of different magnitudes. Autoimmune phenomena have been reported with this treatment. In this paper, we describe cases of ALT/GGT flares during Peg-IFN plus ribavirin treatment, which related to the appearance of anti-Golgi antibody and disease progress. METHODS: We investigated three patients with hepatitis C and severe ALT/GGT flares during Peg-IFN and ribavirin treatment coinciding with anti-Golgi complex antibody as the only marker of autoimmunity. We then reviewed the medical files and tested anti-Golgi antibody in stored sera from 25 patients treated with conventional IFN and in 14 patients treated with Peg-IFN. RESULTS: The three patients were male, over 45 years of age; all were relapsers and non-responders. Anti-Golgi antibody was positive during treatment coinciding with ALT/GGT flares but with hepatitis C virus (HCV)-RNA negativity, disappearing after stopping treatment, with normalization of ALT/AST levels. One patient had progression of fibrosis from F2 to F3 despite negativity of HCV-RNA. In the last group, only two patients treated with Peg-IFN experienced ALT/GGT flares but without anti-Golgi antibody CONCLUSIONS: The presence of anti-Golgi complex antibody could be a marker of a temporary autoimmune phenomenon and progressive disease.

Incomplete septal cirrhosis: an enigmatic disease.

UNLABELLED: Incomplete septal cirrhosis is a form of macronodular cirrhosis characterized by fine and incomplete septa, which delimit rudimentary regeneration nodules. Its etiopathogeny is uncertain and is associated with various diseases such as regenerative nodular hyperplasia, idiopathic portal hypertension, and partial non-cirrhotic nodular transformation, as well as with progression and regression of cirrhosis of any etiology. Few studies are available in the literature describing the clinical and biological characteristics of incomplete septal cirrhosis. GOAL: The objective of the present descriptive study was to study this entity in the city of Salvador, Bahia, Brazil, and to compare the histopathological, biological and clinical data obtained with those reported in the specialized literature. MATERIALS AND METHODS: We reviewed eight cases of incomplete septal cirrhois of varieties etiologies. Hepatitis C, autoimmune hepatitis, alcoholic liver disease and criptogenic liver disease were present in our cases. Fibrosis progression as well as cirrhosis regression could be identified in these patients. CONCLUSIONS: We concluded that Incomplete septal cirrhosis is not a disease itself but it could be considered as a stage of progression and regression of liver fibrosis.

Association between skin parasitism and a granulomatous inflammatory pattern in canine visceral leishmaniosis.

In this work we examined 76 stray dogs from an area of endemic visceral leishmaniosis, in order to determine whether the presence of skin inflammation or a specific inflammatory pattern could be taken as indicative of infection with Leishmania chagasi, and whether the parasite burden in the skin could be associated with the intensity or the nature of the inflammatory process. Inflammatory infiltrates were observed in the skin of 51 out of 55 animals with diagnosis of leishmaniosis, and in 17 out of 21 animals without signs of infection. Amastigotes were identified in the skin of 29 out of the 55 animals with diagnosis of leishmaniosis. Granuloma and a monomorphic macrophage inflammatory infiltrate, and not a mixed focal or mixed diffuse inflammation, were significantly associated with skin parasitism, both in terms of frequency ( P=0.015 in the Chi-square test) and intensity ( P=0.005 in the Kruskal-Wallis test). A low parasite burden was associated with a multifocal inflammatory pattern.

Clinical and histopathological features of NASH in workers exposed to chemicals with or without associated metabolic conditions.

BACKGROUND/AIMS: Non-alcoholic steatohepatitis (NASH) has been associated with exposure to chemicals among workers from an industrial complex in Brazil. We investigated the NASH profile of these individuals associated or not with metabolic conditions. METHODS: Eighty-four patients with NASH were classified into three groups: G1, 31 patients exposed to chemicals (benzene, xylene, vinyl chloride and others); G2, 30 exposed patients who also presented with obesity, hyperlipidemia and diabetes; and G3, 23 non-exposed patients who presented with metabolic conditions. RESULTS: G1 and G2 were similar in terms of gender (97% and 100% males) and age (37+/-5.4 and 39+/-6.5 years). In G3, 74% were males and the age was 48+/-3.4 years (P<0.05). In G2, obesity was present in 26.6%, hyperlipidemia in 66.6% and diabetes in 6.6%. In G3, obesity was observed in 43.4%, hyperlipidemia in 30.4% and diabetes in 26%. Macro- and microsteatosis were observed in 100% of cases. Perisinusoidal fibrosis was observed in 71% patients in G1, 80% in G2 and 52% in G3 (P<0.05). Histological evidence of cholestasis was present in 53% of cases in G1, 50% in G2 and 13% in G3 (P<0.05). CONCLUSIONS: Exposure to chemicals appears to be an independent risk factor for NASH that presents a peculiar profile. It is more frequently seen in men younger than non-exposed ones. Steatosis, fibrosis and cholestasis were frequent histological findings. Co-existing metabolic factors did not seem to influence clinical or histopathological presentation.