Autochthonous hepatitis E as a cause of acute-on-chronic liver failure and death: histopathology can be misleading but transaminases may provide a clue.

BACKGROUND AND AIM: Acute decompensation and death have been observed in patients with acute hepatitis E virus (HEV) infection and preexisting liver cirrhosis. However, the clinical, laboratory and histological features need to be fully characterised. METHODS: Some of us recently described the histological presentation of hepatitis E in a large panel of liver tissue specimens. Here, we conducted a case-control study to investigate the clinical and laboratory features of the subset of patients with HEV-related acute-on-chronic liver failure (ACLF) and death. Each patient was matched to three control patients with histologically confirmed severe alcoholic hepatitis based on sex, age, total bilirubin, INR, serum creatinine and MELD score on admission. RESULTS: Of 5 patients who died in a context of HEV-related ACLF, 3 (60%) were male and the median age was 66 years (range 51–76). Median alanine aminotransferase (ALT) at presentation was 2610 U/l (range 705–3134) and aspartate aminotransferase (AST) 2818 U/l (range 1176–8611). Liver function was heavily altered in all patients. Histological analyses revealed steatohepatitis on a background of cirrhosis, suggestive of an alcoholic or nonalcoholic origin. Based on histopathology, alcoholic hepatitis was initially suspected in two patients and corticosteroid treatment was initiated. Ribavirin was started in four patients. Median time from hospitalisation to death was 17 days (range 6–25 days). AST levels in patients with HEV-related ACLF were significantly higher as compared to the matched patients with severe alcoholic hepatitis. CONCLUSION: Typical histopathological features of viral hepatitis may be absent in ACLF caused by HEV infection. HEV infection should be sought in acute decompensation of cirrhosis and ACLF even in the absence of histological changes suggesting viral infection.

Controlled attenuation parameter for the assessment of liver steatosis in comparison with liver histology: a single-centre real life experience.

BACKGROUND AND AIMS: Accurate diagnosis and staging of non-alcoholic fatty liver disease are essential for the management of this disorder. Controlled attenuation parameter (CAP) has been suggested as a new noninvasive measurement made during transient elastography to assess liver steatosis. The aim of this study was to evaluate CAP as a diagnostic tool for identifying the presence and degree of hepatic steatosis in consecutive patients in an outpatient liver unit of a tertiary centre. METHODS: Between March 2015 and August 2016, all patients who underwent liver biopsy underwent liver stiffness measurement with simultaneous CAP determination using the FibroScan® M or XL probe. Steatosis, inflammatory activity and fibrosis were assessed using the histological SAF scoring system. In addition, fibrosis was scored according to the METAVIR system, and body mass index (BMI) and the underlying liver disease were also recorded. RESULTS: 224 patients were included in the analysis; 146 (65.2%) were male. Steatosis grades were distributed as follows: S0 n = 85 (37.9%), S1 n = 82 (36.6%), S2 n = 33 (14.7%), S3 n = 24 (10.7%). Mean BMI was 26.8 kg/m2, for the S0 group 24.9 kg/m2, S1 26.5 kg/m2, S2 27.3 kg/m2 and S3 32.5 kg/m2. The CAP differed significantly between steatosis groups S0 to S3. The area under receiver operating characteristics curve for S0 vs S1–S3 was 0.78, for S0/1 vs S2/3 0.83 and for S0–2 vs S3 0.82. Calculated cut-off values were 258.5 dB/m for S0 vs S1–3, 282.5 dB/m for S0/1 vs S2/3 and 307.5 dB/m for S0–2 vs S3. CONCLUSIONS: CAP values are strongly associated with the degree of steatosis irrespective of the underlying liver disease. Integrating CAP measurements in the standard work-up may identify patients with NAFLD.  .

Kidney Injury by Variants in the COL4A5 Gene Aggravated by Polymorphisms in Slit Diaphragm Genes Causes Focal Segmental Glomerulosclerosis.

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.

Visualization of hepatitis E virus RNA and proteins in the human liver.

BACKGROUND & AIMS: Although hepatitis E constitutes a substantial disease burden worldwide, surprisingly little is known about the localization of hepatitis E virus (HEV) in the human liver. We therefore aimed to visualize HEV RNA and proteins in situ. METHODS: A panel of 12 different antibodies against HEV open reading frame (ORF) 1-3 proteins was evaluated for immunohistochemistry (IHC) and two probes for in situ hybridization (ISH) in formalin-fixed, paraffin-embedded (FFPE) HuH7 cells transfected with HEV ORF1-3 expression vectors. IHC (and partly ISH) were then applied to Hep293TT cells replicating infectious HEV and liver specimens from patients with hepatitis E (n=20) and controls (n=134). RESULTS: Whereas ORF1-3 proteins were all detectable in transfected, HEV protein-expressing cells, only ORF2 and 3 proteins were traceable in cells replicating infectious HEV. Only the ORF2-encoded capsid protein was also unequivocally detectable in liver specimens from patients with hepatitis E. IHC for ORF2 protein revealed a patchy expression in individual or grouped hepatocytes, generally stronger in chronic compared to acute hepatitis. Besides cytoplasmic and canalicular, ORF2 protein also displayed a hitherto unknown nuclear localization. Positivity for ORF2 protein in defined areas correlated with HEV RNA detection by ISH. IHC was specific and comparably sensitive as PCR for HEV RNA. CONCLUSIONS: ORF2 protein can be reliably visualized in the liver of patients with hepatitis E, allowing for sensitive and specific detection of HEV in FFPE samples. Its variable subcellular distribution in individual hepatocytes of the same liver suggests a redistribution of ORF2 protein during infection and interaction with nuclear components. LAY SUMMARY: The open reading frame (ORF) 2 protein can be used to visualize the hepatitis E virus (HEV) in the human liver. This enabled us to discover a hitherto unknown localization of the HEV ORF2 protein in the nucleus of hepatocytes and to develop a test for rapid histopathologic diagnosis of hepatitis E, the most common cause of acute hepatitis worldwide.

Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma.

BACKGROUND: Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma. The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis. CASE PRESENTATION: We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy. CONCLUSION: We are the first to describe pembrolizumab-related minimal change disease (MCD). Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected.

Surgical resection of isolated adrenal metastases in patients with non-small cell lung cancer: a single-institution experience and review of the literature.

BACKGROUND: In non-small cell lung cancer (NSCLC), the benefits of resection of solitary adrenal metastases for survival and the identification of patients most likely to benefit from adrenalectomy are unknown. PATIENTS AND METHODS: We retrospectively reviewed clinico-pathological factors and outcomes in 4 NSCLC patients treated with adrenalectomy at our centre. We reviewed the published literature with a focus on long-term survivors in order to formulate treatment recommendations. RESULTS: Local pathological staging showed stages IA-IIA. All had a performance status (PS) of 0. The median age was 56 years (range: 53-58 years). Adrenal metastases were detected by positron emission tomography-computed tomography (PET-CT) in 3 patients. Median time from lobectomy to occurrence of metachronous adrenal metastases was 12.3 months (11-14 months). The perioperative mortality was zero. All patients recurred systemically after adrenalectomy within 2-49 months. 3 patients died due to systemic progression 6-15 months after adrenalectomy. 1 patient is alive with pulmonary relapse 49 months after adrenalectomy. CONCLUSIONS: Resection of solitary adrenal metastases in selected good-PS NSCLC patients with minimal local nodal involvement from the primary tumour is associated with low morbidity and may offer a chance for long-term disease-free survival in a small subset of patients. Careful pre-operative staging including PET-CT is warranted.

Involvement of drug-specific T cells in acute drug-induced interstitial nephritis.

Drug-induced interstitial nephritis can be caused by a plethora of drugs and is characterized by a sudden impairment of renal function, mild proteinuria, and sterile pyuria. For investigation of the possible pathomechanism of this disease, drug-specific T cells were analyzed, their function was characterized, and these in vitro findings were correlated to histopathologic changes that were observed in kidney biopsy specimens. Peripheral blood mononuclear cells from three patients showed a proliferative response to only one of the administered drugs, namely flucloxacillin, penicillin G, and disulfiram, respectively. The in vitro analysis of the flucloxacillin-reactive cells showed an oligoclonal immune response with an outgrowth of T cells bearing the T cell receptor Vbeta9 and Vbeta21.3. Moreover, flucloxacillin-specific T cell clones could be generated from peripheral blood, they expressed CD4 and the alphabeta-T cell receptor, and showed a heterogeneous cytokine secretion pattern with no clear commitment to either a Th1- or Th2-type response. The immunohistochemistry of kidney biopsies of these patients revealed cell infiltrations that consisted mostly of T cells (CD4+ and/or CD8+). An augmented presence of IL-5, eosinophils, neutrophils, CD68+ cells, and IL-12 was observed. In agreement with negative cytotoxicity assays, no cytotoxicity-related molecules such as Fas and perforin were detected by immunohistochemistry. The data indicate that drug-specific T cells are activated locally and orchestrate a local inflammation via secretion of various cytokines, the type of which depends on the cytokine pattern secreted and which probably is responsible for the renal damage.

Dieulafoy's disease of the lung: a potential disaster for the bronchoscopist.

Dieulafoy's disease of the lung is very rare. We present 2 cases, which are, to our knowledge, the 9th and 10th cases reported in the literature. Haemoptysis is the leading symptom of Dieulafoy's lesion of the lung. In spite of its rareness, the lesion is relevant to the bronchoscopist because a biopsy of the unobtrusive but characteristic bronchial manifestation can precipitate profuse arterial bleeding with a fatal outcome. The bleeding can occur immediately after the biopsy and/or after an interval of up to 12 days. Angiographic images document that this vascular malformation is based on a left-to-right shunt, with a bronchial artery draining into a pulmonary artery. Endobronchial ultrasound may be helpful in detecting the vascular nature of the lesion.

Resection of skin metastases from gastric carcinoma with long-term follow-up: an unusual clinical presentation.

BACKGROUND: Skin metastases from gastric cancer are rare and generally occur at a very late stage in the course of the disease. CASE REPORT: A 60-year-old patient with localized adenocarcinoma of the cardia (stage II) was primarily treated with extended total gastrectomy with transhiatal resection of the distal esophagus. 6 isolated skin metastases occurred on the head and on the thigh 2 years later. These lesions where all surgically removed. Morphologically and according to an extensive immunohistochemical comparison the skin lesions and the primary tumor were identical. The patient presented with dysphagia more than 6 years after the primary diagnosis, and a local recurrence was diagnosed. Again a surgical procedure was chosen and a transthoracal esophagectomy with intrathoracic esophagojejunostomy was performed. This patient remains free of symptoms and is clinically in complete remission 7.5 years after the primary diagnosis. CONCLUSION: We report a long-term disease-free survival of a patient with isolated cutaneous metastases of a gastric cancer. Usually the prognosis after occurrence of metastases to the skin is poor, but long-term survival after systemic therapy has been reported. This patient is clinically in remission more than 5 years after surgical resection of several cutaneous metastases and after successful resection of a local recurrence more than 1 year ago. One should be aware of such unusual clinical courses of a disease, and that the prognosis can deviate significantly from the average when the pattern of metastasis is unusual.

Treatment of a case of primary retroperitoneal mucinous cystadenocarcinoma: is adjuvant hysterectomy and bilateral salpingo-oophorectomy justified?

OBJECTIVE: We present a case of primary retroperitoneal mucinous cystadenocarcinoma in a 38-year-old woman. STUDY DESIGN: The tumor was resected with a segment of adjacent descending colon. Five years after the operation, the patient is well, without evidence of recurring disease, based on clinical investigation and modern imaging techniques. RESULTS: In the light of the literature, it appears most likely that this rare tumor is caused by coelomic metaplasia. On the basis of the histopathologic findings in our case and the reports from the literature, we recommend radical tumor excision en bloc with all infiltrated adjacent structures. CONCLUSION: Added removal of unaffected uterus and adnexes makes young women infertile and climacteric and is not yet validated by long-term results.

Renal tubular epithelial expression of the costimulatory molecule B7RP-1 (inducible costimulator ligand).

MHC class II-expressing renal tubular epithelial cells (TEC) are able to present foreign peptide antigens to T cells. The costimulatory signals that are required for effective T cell activation upon antigen presentation by TEC have not been characterized. Various cultured TEC lines were examined for expression of the recently described costimulatory molecule B7RP-1 (B7h), a ligand of the T cell molecule inducible costimulator (ICOS), and expression was compared with that of B7.1, B7.2, and CD40. B7RP-1 and CD40 were abundantly expressed by cultured murine and human TEC, whereas B7.1 and B7.2 could not be detected. Stimulation with lipopolysaccharide or tumor necrosis factor-alpha did not induce B7.1 or B7.2 expression and did not alter B7RP-1 expression. Interestingly, interleukin-2 production by T cell hybridomas after antigen presentation by TEC was enhanced by blocking antibodies to B7RP-1 and ICOS. In contrast, blocking antibodies to B7RP-1 or ICOS exerted inhibitory effects on anti-CD3-activated murine splenocyte proliferation. Immunohistochemical staining of normal human kidneys demonstrated strong constitutive B7RP-1 expression in distal tubules, collecting ducts, and urothelium. In human kidneys with allograft rejection or interstitial nephritis, distinct B7RP-1 staining was also detected in proximal tubules, in areas of mononuclear infiltration. In conclusion, the B7RP-1/ICOS pathway negatively regulates T cell activation upon MHC class II-restricted antigen presentation by TEC. Because B7RP-1 is also expressed by tubules in vivo, it can be speculated that the B7RP-1/ICOS pathway could play an inhibitory role in TEC-mediated immune activation in the kidney.

Orbital involvement as the first manifestation in classic Wegener's granulomatosis.

Wegener's granulomatosis (WG) is a chronic, focal, necrotizing granulomatous angiitis, which mainly affects the upper respiratory tract, the lungs and the kidneys. We present the case of a 26-year-old female patient complaining of pain and increasing swelling of the upper right eyelid with exophthalmos and diplopia as the first manifestation of a classic WG. Computer tomography revealed a homogeneous tumor arising from the right lacrimal gland. Chest x-ray revealed a tumor of the right lung. Microhematuria disclosed a slight renal involvement. Positive ANCA titer and C-ANCA anti-PR3, as well as a positive lung biopsy, confirmed the diagnosis of WG. Treatment with prednisone and cyclophosphamide was initiated. One year later, the patient's condition was good, and the ophthalmological examination was normal. WG should be considered in the differential diagnosis of an orbital tumor. In some rare cases, orbital disease can be the first clinical manifestation of the classic form of WG.