PRAME immunostain expression in sebaceous lesions, cutaneous carcinomas and adnexal structures.

The use of immunostain for PRAME antigen is well established for cutaneous melanolocytic lesions. However, its staining in other cutaneous structures and lesions is under reported. This study assessed PRAME staining in a large cohort of normal skin tissue, sebaceous lesions, and cutaneous carcinomas to better delineate patterns of PRAME immunoreactivity. PRAME immunostaining was performed on sections of sebaceous lesions and tissue microarrays of basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). Normal cutaneous adnexal structures were assessed on the sections of sebaceous lesions. For sebaceous lesions and non-lesional sebaceous glands, PRAME immunostaining was assessed for mature, germinative and sebocytes independently. A total of 193 sebaceous lesions, 64 BCCs and 35 SCCs were stained for PRAME immunostain. Staining pattern was predominantly cytoplasmic in normal apocrine glands, germinative sebocytes of sebaceous glands, and hair germs (p<0.001). Lesional sebocytes did not show different staining compared to normal sebaceous glands (p>0.05). Rare nuclear staining was observed in the normal epidermis (0.6%) and junctional melanocytes (4.1%). BCC, SCC and sebaceous carcinoma all showed low levels of PRAME immunoreactivity with variable proportions of cases demonstrating nuclear staining (BCC 59.4%, SCC 37.1%, sebaceous carcinoma 5.3%). PRAME immunostaining is positive in germinative sebocytes, various cutaneous structures and carcinomas. Nuclear staining, identical to melanoma, was observed in normal epidermis, junctional melanocytes, BCCs, SCCs, and sebaceous carcinomas. The pattern of PRAME staining in the skin must be recognised to avoid pitfalls in interpretating PRAME immunostain.

High Prevalence of Late-Onset Fabry Cardiomyopathy in a Cohort of 499 Non-Selective Patients with Left Ventricular Hypertrophy: The Asian Fabry Cardiomyopathy High-Risk Screening Study (ASIAN-FAME).

Left ventricular hypertrophy (LVH) caused by cardiac variant Fabry disease (FD) is typically late-onset and may mimic LVH caused by abnormal loading conditions. We aimed to determine the prevalence of FD in a non-selective patient population of everyday practice presenting with LVH, including those with hypertension and valve disease. We measured plasma alpha-galactosidase A activity using dried blood spot tests in 499 (age = 66 ± 13 years; 336 men) Hong Kong Chinese patients with LVH defined as maximal LV septal/posterior wall thickness ≥13 mm on echocardiography. Patients with low enzyme activity underwent mutation analysis of the GLA gene. Eight (age = 53-74 years; all men) unrelated patients (1.6%) had low plasma alpha-galactosidase A activity (0.57 ± 0.27 µmol/L wb/hr) and all were confirmed to have the GLA IVS4 + 919G > A mutation. FD patients presented with heart failure (n = 5), heart block (n = 2), ventricular tachycardia (n = 1), chest pain (n = 3), and/or murmur (n = 1). Uncontrolled hypertension (n = 4) and/or severe mitral/aortic valve pathology (n = 2) were frequent. Ethnic subgroups included Teochew (n = 5), Canton (n = 2), and Wenzhou (n = 1). Endomyocardial biopsy (n = 6) revealed hypertrophic myocytes with vacuolization and dense lamellar bodies. Late-onset IVS4 + 919G > A FD is prevalent among Chinese LVH patients, and should be considered as a cause of LVH in adult patients even when hypertension and/or valve pathology are present.

Screening for Fabry Disease in patients with unexplained left ventricular hypertrophy.

Fabry Disease (FD) is a systemic disorder that can result in cardiovascular, renal, and neurovascular disease leading to reduced life expectancy. FD should be considered in the differential of all patients with unexplained left ventricular hypertrophy (LVH). We therefore performed a prospective screening study in Edmonton and Hong Kong using Dried Blood Spot (DBS) testing on patients with undiagnosed LVH. Participants found to have unexplained LVH on echocardiography were invited to participate and subsequently subjected to DBS testing. DBS testing was used to measure α-galactosidase (α-GAL) enzyme activity and for mutation analysis of the α-galactosidase (GLA) gene, both of which are required to make a diagnosis of FD. DBS testing was performed as a screening tool on patients (n = 266) in Edmonton and Hong Kong, allowing for detection of five patients with FD (2% prevalence of FD) and one patient with hydroxychloroquine-induced phenocopy. Left ventricular mass index (LVMI) by GLA genotype showed a higher LVMI in patients with IVS4 + 919G > A mutations compared to those without the mutation. Two patients were initiated on ERT and hydroxychloroquine was discontinued in the patient with a phenocopy of FD. Overall, we detected FD in 2% of our screening cohort using DBS testing as an effective and easy to administer screening tool in patients with unexplained LVH. Utilizing DBS testing to screen for FD in patients with otherwise undiagnosed LVH is clinically important due to the availability of effective therapies and the value of cascade screening in extended families.

Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B.

BACKGROUND AND AIMS: Concurrent fatty liver in hepatitis B virus (HBV)-infected patients without significant alcohol intake is a frequent and increasingly alarming problem because of the non-alcoholic fatty liver disease pandemic. The risk of HBV-related hepatocellular carcinoma (HCC) development was increased by concomitant obesity and diabetes. Direct evidence of the hepatocarcinogenic effect of fatty liver in chronic HBV remains elusive. We aimed to evaluate the risk of concurrent histologically proven fatty liver in HBV hepatocarcinogenesis. METHODS: We conducted a retrospective cohort study on a liver biopsy cohort of HBV-infected patients without significant alcohol intake to evaluate the prevalence of concurrent histologically proven fatty liver and its association with subsequent HCC development. We also examined nine polymorphisms on six non-alcoholic fatty liver disease-related candidate genes (ADIPOQ, APOC3, GCKR, LEPR, PNPLA3, and PPARG). RESULTS: Among 270 HBV-infected patients, concurrent fatty liver was found in 107 patients (39.6%) and was associated with metabolic risks, cirrhosis (P = 0.016) and PNPLA3 rs738409 CG/GG genotype (P = 0.002). At a median follow-up of 79.9 months, 11 patients (4.1%) developed HCC, and nine of them had concurrent fatty liver. By multivariable Cox analysis, concurrent fatty liver (HR 7.27, 95% confidence interval: 1.52-34.76; P = 0.013), age, cirrhosis, and APOC3 rs2854116 TC/CC genotype (HR 3.93, 95% confidence interval: 1.30-11.84; P = 0.013) were independent factors predicting HCC development. CONCLUSIONS: Concurrent fatty liver is common in HBV-infected patients and an independent risk factor potentiating HBV-associated HCC development by 7.3-fold. The risk of HBV-related HCC is increased by APOC3 gene polymorphism, and further characterization is required by its role.

Neonatal Abdominal Hemangiomatosis: Propranolol beyond Infantile Hemangioma.

Hemangioma is the most common vascular tumor of infancy; presentation is often as cutaneous infantile hemangioma (IH). Cutaneous hemangioma is a clinical diagnosis. Most IHs follow a benign course, with complete involution without treatment in the majority of cases. Visceral hemangioma often involves the liver and manifests as a life-threatening disorder. Hepatic hemangiomas may be associated with high output cardiac failure, coagulopathy, and hepatomegaly which generally develop between 1 and 16 weeks of age. Mortality has been reportedly high without treatment. We report a rare case of a male infant with neonatal hemangiomatosis with diffuse peritoneal involvement, which mimicked a malignant-looking tumor on imaging, and discuss therapeutic options and efficacy. Propranolol is efficacious for IH but generally not useful for other forms of vascular hemangiomas, tumors, and malformations. In our case of neonatal peritoneal hemangiomatosis, propranolol appears to have halted the growth and possibly expedite the involution of the hemangiomatosis without other treatments.

New simple prognostic score for primary biliary cirrhosis: Albumin-bilirubin score.

BACKGROUND AND AIM: Serum albumin and bilirubin are the most significant independent prognostic factors to predict hepatic events in patients with primary biliary cirrhosis (PBC). We aimed to investigate the prognostic significance of a new prognostic score, the albumin-bilirubin (ALBI) score, among PBC patients. METHODS: In a retrospective longitudinal cohort of 61 Chinese PBC patients with follow-up period up to 18.3 years, the prognostic performance of the ALBI in prediction of hepatic events was compared with other well-established prognostic scores: Child-Pugh score, model of end-stage liver disease, Mayo risk score, Yale, European, and Newcastle models. RESULTS: Fifteen patients (24.6%) developed hepatic events during follow-up. The c-index (0.894) and χ(2) by likelihood ratio test (36.34) of the ALBI score were highest in comparison to other models. The ALBI score was the only independent prognostic factor by multivariate analysis and its adjusted hazard ratio of developing hepatic event was 27.8 (P < 0.001). There were three prognostically different groups stratified by the ALBI score: ALBI grade 1 (≤ -2.60), grade 2 (> -2.60 to -1.39), and grade 3 (> -1.39) groups. The 2-, 5-, and 10-year event-free survivals for grade 1, grade 2, and grade 3 groups were 100.0% versus 100.0% versus 57.1%, 100.0% versus 88.5% versus 14.3%, and 100.0% versus 81.7% versus 0.0%, respectively (P < 0.001). CONCLUSION: The ALBI score is readily derived from a blood test without using those factors evaluated subjectively or obtained by invasive procedures. It is an independent prognostic factor for PBC patients and provides better/similar prognostic performance compared with other prognostic scores.

Age and etiology of childhood epidermolysis bullosa mortality.

Epidermolysis bullosa (EB) is a heterogeneous group of congenital blistering diseases that are usually present in the neonatal period. They are characterized by blister formation in response to rubbing or frictional trauma. EB is classified into three major categories, each with many subtypes based on the precise location at which separation or blistering occurs, namely epidermolysis bullosa simplex (EBS), junctional epidermolysis bullosa (JEB), and dystrophic epidermolysis bullosa (DEB). We describe the causes and ages of death of three cases of EB in Hong Kong. A 24-year-old male with EBD diagnosed in the neonatal period lived a withdrawn life after completing secondary school and died of metastaic squamous cell carcinoma. Two neonates of consanguineous Pakistani parents, one with JEB and the other with EB-Pyloric Atresia variant, died of sepsis in infancy. We performed an extensive literature review of the causes and ages of death of these diseases. EB is a heterogeneous inherited blistering skin disease associated with significant morbidity and mortality. EBS is occasionally associated with death at early ages with sepsis. Patients with JEB usually died of sepsis at young age. DEB patients often survive to adulthood and die of cardiopulmonary and renal complications. Squamous cell carcinoma and metastases are unique in DEB.

Evaluation of histological staging systems for primary biliary cirrhosis: correlation with clinical and biochemical factors and significance of pathological parameters in prognostication.

AIMS: A new Japanese histological staging system for primary biliary cirrhosis (PBC) has been proposed. We aimed to evaluate the efficacies of the Scheuer, Ludwig and Japanese staging systems, with emphasis on their clinical and biochemical correlations and prognostic significances. METHODS AND RESULTS: We conducted a retrospective review of a cohort of 58 Chinese PBC patients, with follow-up of up to 16.9 years. All three systems correlated well with prognostically significant parameters, namely serum bilirubin, Mayo scores and model for end-stage liver disease (MELD) score. Only the Japanese staging system was associated with Child-Pugh score, which was the single independent prognostic factor for liver-related events (log-rank P < 0.001; Cox proportional hazard ratio (HR) 6.723, P < 0.001). The Japanese system (log-rank P = 0.007; Cox proportional HR 10.400, P = 0.025) predicted liver-related events, while Scheuer (log-rank P = 0.112) and Ludwig (log-rank P = 0.147) systems did not. The copper-associated protein (CAP) deposition score, a component of the Japanese system, was the most powerful histological prognostic parameter (log-rank P < 0.001; Cox proportional HR 99.534, P = 0.049) and provided extra prognostic values in additional to serum albumin, serum bilirubin, Child-Pugh score, Mayo scores and MELD score. CONCLUSION: The Japanese staging system is more effective than classical systems. The degree of CAP deposition is an essential prognostic histological parameter.

Non-alcoholic fatty liver disease: spectral patterns observed from an in vivo phosphorus magnetic resonance spectroscopy study.

BACKGROUND & AIMS: Liver biopsy is the gold standard for diagnosing non-alcoholic fatty liver disease (NAFLD) but with practical constraints. Phosphorus magnetic resonance spectroscopy ((31)P-MRS) allows in vivo assessment of hepatocellular metabolism and has shown potential for biochemical differentiation in diffuse liver disease. Our aims were to describe spectroscopic signatures in biopsy-proven NAFLD and to determine diagnostic performance of (31)P-MRS for non-alcoholic steatohepatitis (NASH). METHODS: (31)P-MRS was performed in 151 subjects, comprised of healthy controls (n=19) and NAFLD patients with non-NASH (n=37) and NASH (n=95). Signal intensity ratios for phosphomonoesters (PME) including phosphoethanolamine (PE), phosphodiesters (PDE) including glycerophosphocholine (GPC), total nucleotide triphosphate (NTP) including α-NTP, and inorganic phosphate (Pi), expressed relative to total phosphate (TP) or [PME+PDE] and converted to percentage, were obtained. RESULTS: Compared to controls, both NAFLD groups had increased PDE/TP (p<0.001) and decreased Pi/TP (p=0.011). Non-NASH patients showed decreased PE/[PME+PDE] (p=0.048), increased GPC/[PME+PDE] (p<0.001), and normal NTP/TP and α-NTP/TP. Whereas, NASH patients had normal PE/[PME+PDE] and GPC/[PME+PDE], but decreased NTP/TP (p=0.004) and α-NTP/TP (p<0.001). The latter was significantly different between non-NASH and NASH (p=0.047) and selected as discriminating parameter, with area under the receiver-operating characteristics curve of 0.71 (95% confidence interval, 0.62-0.79). An α-NTP/TP cutoff of 16.36% gave 91% sensitivity and cutoff of 10.57% gave 91% specificity for NASH. CONCLUSIONS: (31)P-MRS shows distinct biochemical changes in different NAFLD states, and has fair diagnostic accuracy for NASH.

Intrarenal expression of microRNAs in patients with IgA nephropathy.

MicroRNAs (miRNAs) are noncoding, single-stranded RNA molecules that have important roles in a number of physiological and pathological processes. Previous studies have proved that miRNAs targeting ZEB1 and ZEB2 may repress epithelial-to-mesenchymal transition. In this work, we studied the intrarenal expression of miR-200 family, miR-205 and miR-192 in patients with immunoglobulin A (IgA) nephropathy. We studied 43 patients with biopsy-proven IgA nephropathy (IgA group). The intrarenal expression of miRNAs was quantified and compared with that of 15 patients with noninflammatory glomerulosclerosis (GS group) and 20 patients with nephrectomy for kidney cancer as controls (CTL group). The level of intrarenal miR-200c was downregulated, whereas the levels of intrarenal miR-141, miR-205 and miR-192 were upregulated in IgA but not GS group. Proteinuria significantly correlated with the intrarenal expression of miR-200c (r=-0.324, P=0.011) and glomerular filtration rate (GFR) significantly correlated with the intrarenal expression of miR-205 (r=-0.280, P=0.030). The degree of tubulointerstitial scarring correlated with miR-205 expression (r=0.389, P=0.021), whereas glomerulosclerosis correlated with miR-192 expression (r=-0.311, P=0.045). The rate of GFR decline significantly correlated with the intrarenal expression of miR-192 (r=0.373, P=0.015). The intrarenal expression of E-cadherin significantly correlated with the intrarenal expression of miR-200c (r=0.392, P=0.002). The results show that intrarenal expression of miR-200c, miR-141, miR-205 and miR-192 was diversely regulated and correlated with disease severity and progression in patients with IgA nephropathy. These miRNA species may be important in the pathogenesis and progression of IgA nephropathy.

Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B.

BACKGROUND AND AIMS: The proposed cut-off values for the degree of fibrosis as assessed by liver stiffness measurement (LSM) might not be applicable in severe acute exacerbation of chronic hepatitis B (CHB). We aimed to assess the effect of necroinflammatory activity on LSM in this condition. METHODS: We prospectively recruited consecutive patients with severe acute exacerbation of CHB (alanine aminotransferase or ALT > 10x upper limit of normal). The relationship of ALT levels and LSM were serially assessed and liver biopsy was carried out after ALT normalization. RESULTS: Eleven patients (10 male, median age 43 years) were followed up for 25 weeks; nine patients received antiviral therapy. Overall, LSM was positively correlated with ALT levels (r = 0.67, P < 0.001). At initial presentation, the median serum ALT and LSM was 1136 (581-2210) IU/L and 26.3 (11.1-33.3) kPa. A progressive reduction in LSM was observed during subsequent visits in parallel with the reduction of ALT levels. At the last visit, the median ALT was 27 (11-52) IU/L and LSM was 7.7 (4.7-10.8) kPa. Among the five patients who had liver biopsy carried out at week 25, four patients had F2 fibrosis (LSM 5.7-8.1 kPa) and one patient had F3 fibrosis (LSM 8.6 kPa). CONCLUSIONS: LSM using transient elastography with the current proposed cut-off values might misdiagnose liver cirrhosis in patients suffering from severe acute exacerbation of CHB. LSM should be assessed after normalization of ALT levels in order to accurately assess the degree of fibrosis.

Retrocapsular lens matter in uneventful phacoemulsification: does it really exist?

PURPOSE: To have the first cytopathological evaluation of any lens matter fragments within retrocapsular anterior vitreous in those patients undergone uneventful phacoemulsification in Prince of Wales Hospital, Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong. METHODS: Thirty patients with cataracts and various vitreoretinal conditions that required combined surgery were recruited. After the uneventful clear corneal phacoemulsification, three sclerotomies including infusion port were created with cautions against any inadvertent leakage of vitreal content. The anterior vitreous at retrocapsular space was harvested by a special 'round-the-clock' dry vitrectomy into a special specimen reservoir hub and syringe. The aspirate was immediately fixed in 50% ethanol and together with a masked positive control sent for cytocentrifugation processing. The microscope slides of the anterior vitreal content and control were stained with haematoxylin and eosin and papanicolaou. Positive controls were collected from the effluent fluid of the phaco cassettes right after the phacoemulsification. The samples were masked and examined by an experienced pathologist for any cytopathological evidence of lens matter. RESULTS: Out of 30 patients, three suspicious cases of retrocapsular lens fragment were noted by retroillumination on the operating table. However, all the anterior vitreous specimens were negative for lens matter whereas all the controls were positive after cytopathological verification. CONCLUSIONS: This is the first cytopathological study objectively indicating low likelihood of the postulation that retrocapsular lens matter occurred after uneventful phacoemulsification.

Association of cytokine gene polymorphisms and liver fibrosis in chronic hepatitis B.

BACKGROUND AND AIM: As liver fibrosis is the result of persistent necroinflammation in the liver, pro-inflammatory cytokines secreted in response to cell injury have a central role in the pathogenesis of liver fibrosis. We aimed to investigate the association of cytokine gene polymorphism and liver fibrosis among Chinese patients with chronic hepatitis B. METHODS: Polymorphisms at interleukin-10 (IL-10-627, -1117), interleukin-1-beta (IL-1beta-511, -31, -3964), interleukin-1 receptor antagonist (IL-1RN), and tumor necrosis factor-alpha (TNF-alpha-308, -238) among Chinese chronic hepatitis B patients were determined. Severe liver fibrosis was defined as Ishak fibrosis score = 4 (of 6). RESULTS: Fifty-nine of 273 (22%) patients had severe fibrosis. The distribution of genotypes for IL-10-627 was CC (11%), CA (41%), and AA (48%). The CC genotype at IL-10-627 was protective against severe fibrosis (odds ratio (OR) 0.11; 95% CI 0.014-0.82; P = 0.032). After adjusted for baseline variables, the adjusted OR of CC genotypes at IL-10-627 for severe fibrosis was 0.063 (95% CI 0.06-0.64; P = 0.063). Other gene polymorphisms at IL-1beta, IL-1RN, TNF-alpha, and IL-10 had no significant association with severe fibrosis. Weak linkage disequilibrium was observed between IL-10-627 and IL-10-1117 with linkage disequilibrium coefficient of 0.12 (P < 0.001). The distribution of haplotypes of IL-10-1117 and IL-10-627 was A-A (69%), A-C (26%), and G-C (5%). High and intermediate IL-10 production (A-C and G-C) haplotypes were protective against severe fibrosis (OR 0.62; 95% CI 0.39-0.99; P = 0.046). CONCLUSIONS: High production genotype and haplotypes of IL-10 were associated with less severe liver fibrosis in chronic hepatitis B in Chinese.

Diffuse large B-cell non-Hodgkin's lymphoma associated with bilateral carotid-cavernous fistulas in an elderly woman.

A 74-year-old woman presented with a 2-month history of left proptosis, left eye chemosis, left abducens nerve palsy and cervical lymphadenopathy. She was noted to have bilateral carotid cavernous fistulas and was treated with transvenous coil embolization. The diagnosis of diffuse large B-cell non-Hodgkin's lymphoma was only confirmed 4 months later, despite a high index of suspicion, after clinical deterioration. This is, to our knowledge the first reported case of non-Hodgkin's lymphoma associated with bilateral carotid cavernous fistulas.

Unusual eye signs in Wegener's granulomatosis.

Wegener's granulomatosis is a rare necrotising vasculitis not easily diagnosed due to the obscurity of its diverse clinical features. Despite its comparatively low incidence, the unusual ophthalmic manifestations seen in this disease warrant extra caution from attending rheumatologists. In this case, bilateral peripheral ulcerative keratitis preceded any systemic symptoms. Timely recognition of the significance of this ophthalmic complaint and prompt ophthalmological consultation can help achieve early diagnosis and treatment of this potentially fatal rheumatological disease.