Marijana Ćorić

Lysosomal acid lipase deficiency – An under-recognized cause of dyslipidaemia and liver dysfunction

Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have the most rapidly progressive disease, developing signs and symptoms in the first weeks of life and rarely surviving beyond 6 months of age. Children and adults typically present with some combination of dyslipidaemia, hepatomegaly, elevated transaminases, and microvesicular hepatosteatosis on biopsy. Liver damage with progression to fibrosis, cirrhosis and liver failure occurs in a large proportion of patients. Elevated low-density lipoprotein cholesterol levels and decreased high-density lipoprotein cholesterol levels are common features, and cardiovascular disease may manifest as early as childhood. Given that these clinical manifestations are shared with other cardiovascular, liver and metabolic diseases, it is not surprising that LAL-D is under-recognized in clinical practice. This article provides practical guidance to lipidologists, endocrinologists, cardiologists and hepatologists on how to recognize individuals with this life-limiting disease. A diagnostic algorithm is proposed with a view to achieving definitive diagnosis using a recently developed blood test for lysosomal acid lipase. Finally, current management options are reviewed in light of the ongoing development of enzyme replacement therapy with sebelipase alfa (Synageva BioPharma Corp., Lexington, MA, USA), a recombinant human lysosomal acid lipase enzyme.

Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: A relation with NO-system

Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) reversed congestive heart failure and various arrhythmias, influenced the NO-system and showed no proarrhythmic effect. In therapy analogy, we challenged rats with digitalis, to show attenuation by BPC 157 and the relation between the NO-system and digitalis toxicity. (i). BPC 157 prophylactic effect. Development of cumulative intravenous digitalis toxicity, BPC 157 (50 microg, 10 microg, 10 ng/kg applied intravenously immediately before a methyldigoxin increment regimen (2.0/1.5/1.5/1.0 mg/kg at 15 min-intervals, total dose 6.0 mg/kg/45 min)) reduced the number of ventricular premature beats, prolonged the time before onset of ventricular tachycardia, reduced ventricular tachycardia and AV-block duration (microg-regimes) or reduced mainly the AV-block duration (ng-regimen). (ii). BPC 157 therapy. Advanced methyldigoxin toxicity (6.0 mg/kg i.v. bolus). BPC 157 applied at the 20th second of the grade 3 AV-block shortened AV-blocks, mitigated a further digitalis toxicity course. Ventricular tachycardias were either avoided (50 microg), or markedly reduced (10 microg, 10 ng). Fatal outcome was either avoided (50 microg), reduced (10 microg), or only delayed (10 ng) (iii) BPC 157, L-NAME, l-arginine, L-NAME+l-arginine application. L-NAME-application (5 mg/kg i.p.) aggravated methyldigoxin-arrhythmias. l-arginine (200 mg/kg i.p.) alone had no effect but blunted L-NAME-exaggeration (L-NAME+l-arginine). In this respect, BPC 157 (50 microg/kg i.p.) was prophylactically and therapeutically more effective: the antagonism of L-NAME with BPC 157 produced an effect similar to BPC 157 alone. In conclusion, digitalis-induced arrhythmias in rats could be prevented and counteracted by pentadecapeptide BPC 157, mainly through an interaction with the NO-system.

Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model : Diclofenac-induced gastrointestinal, liver, and encephalopathy lesions

AIMS We attempted to fully antagonize the extensive toxicity caused by NSAIDs (using diclofenac as a prototype). MAIN METHODS Herein, we used the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419), an anti-ulcer peptide shown to be efficient in inflammatory bowel disease clinical trials (PL 14736) and various wound treatments with no toxicity reported. This peptide was given to antagonize combined gastrointestinal, liver, and brain toxicity induced by diclofenac (12.5mg/kg intraperitoneally, once daily for 3 days) in rats. KEY FINDINGS Already considered a drug that can reverse the toxic side effects of NSAIDs, BPC 157 (10 μg/kg, 10 ng/kg) was strongly effective throughout the entire experiment when given (i) intraperitoneally immediately after diclofenac or (ii) per-orally in drinking water (0.16 μg/mL, 0.16 ng/mL). Without BPC 157 treatment, at 3h following the last diclofenac challenge, we encountered a complex deleterious circuit of diclofenac toxicity characterized by severe gastric, intestinal and liver lesions, increased bilirubin, aspartate transaminase (AST), alanine transaminase (ALT) serum values, increased liver weight, prolonged sedation/unconsciousness (after any diclofenac challenge) and finally hepatic encephalopathy (brain edema particularly located in the cerebral cortex and cerebellum, more in white than in gray matter, damaged red neurons, particularly in the cerebral cortex and cerebellar nuclei, Purkinje cells and less commonly in the hippocampal neurons). SIGNIFICANCE The very extensive antagonization of diclofenac toxicity achieved with BPC 157 (μg-/ng-regimen, intraperitoneally, per-orally) may encourage its further use as a therapy to counteract diclofenac- and other NSAID-induced toxicity.

Congenital oral gastrointestinal cyst: an immunohistochemical analysis.

Abstract Cystic lesions of the oral cavity are quite common. Mostly their morphology is that of simple cystic lesions lined by squamous epithelium. Rarely the epithelium may be of another type, e.g. that of gastrointestinal tract. In the English literature in English about 30 cases of oral cysts with gastrointestinal epithelium lining have been reported. This developmental lesion is very rare and is found more frequently in young males. The majority of lesions were reported to occur in the ventral surface of the anterior tongue and extend to the floor of the mouth. Heterotopic gastrointestinal epithelium has been more commonly described in the duodenum, gallbladder, jejunum, Meckel’s diverticulum, ileum, appendix, colon and rectum. We report an oral heterotopic gastrointestinal cyst in a child. A healthy 2-month-old boy had an asymptomatic swelling in the sublingual area that had been present since birth. Under general anesthesia, the patient underwent conservative excision of the cyst. Gross examination of the excised tissue showed a monolocular cystic lesion in the bottom of the oral cavity. Microscopically, the cystic lining mostly resembled intestinal mucosa; in some places, stratified squamous and columnar epithelium was also present. The pathogenesis of this lesion remains uncertain. Several theories have been postulated; the most commonly held suggests that these cysts may be derived from misplacement of embryonic rests.

Correlation between retroperitoneal lymph node size and presence of metastases in nonseminomatous germ cell tumors

Eighty-five patients had staging laparoscopic retroperitoneal lymph node dissection (L-RPLND) for nonseminomatous germ cell tumors at our institution. The largest lymph node size was measured and presence or absence of metastatic disease was determined. A total of 1139 lymph nodes have been removed and in 27 (31.8%) patients, metastases in one or more lymph nodes were detected. There were 338 (29.7%) hilar, 259 (22.7%) paraaortic, 221 (19.4%) interaortocaval, 171 (15%) paracaval, 133 (11.7%) preaortic and 17 (1.5%) precaval lymph nodes. The total number of lymph nodes with metastases was 74 (6.5%), and 1065 (93.5%) nodes did not have any metastases. The average size of a lymph node with metastases was 1.05 (0.3-3), and without metastases it was 0.55 (0.1-2.5) cm, (p<0.001). If we use > 1 cm size of a lymph node as a “cut-off” value for enlargement and presence of metastases, 60% of metastatic lymph nodes would be missed since they were all ≤ 1 cm. Our results have shown that decreasing size of lymph nodes which are considered positive from > 1 cm to 0.7 -0.8 cm can be recommended, with specificity and sensitivity equal 70%.

Renal Complications of Fabry Disease

Fabry disease is a progressive devastating disease caused by absent or deficient activity of lysosomal enzyme alpha-galactosidase A, with progressive accumulation of globotriaosylceramide (GL-3) within lysosomes in a different cell types. Accumulation of GL-3 and related glycosphingolipids in different cell types may create diverse clinical picture depending on the organ which is dominantly affected. Renal pathology progresses in severity with aging. Globotryaosil ceramide deposits may be found in different cell types within the kidney. Deposition within the glomeruli may be found in endothelial cells, mesangial cells, interstitial cells, with the highest level found within the podocytes. Although Fabry disease is not curable at the moment, availability of enzyme replacement therapy made it possible to treat this group of patients. Two formulations of recombinant human alpha-galactosidase A are present on the market: agalsidase alfa and agalsidase beta. Longer follow-up period is necessary to estimate the impact of ERT on mortality. Patients with end-stage renal disease caused by Fabry disease could be safely treated with enzyme replacement therapy regardless of the method of renal replacement therapy.

Immunolocalization and mRNA Expression of Bone Morphogenetic Protein-6 in Human Clear Cell Renal Carcinoma

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β superfamily of proteins. Dysregulation of BMP signaling has been suggested in the carcinogenesis of different organs. We determined BMP-6 mRNA and protein expression in localized human clear cell renal carcinoma (CCRC), obtained from 20 patients who underwent nephrectomy, by the real-time polymerase chain reaction and immunohistochemistry. 15/20 patients exhibited higher BMP-6 mRNA expression in malignant than in healthy renal tissue relative to the PBGD expression (p < 0.05). Immunostaining intensity for BMP-6 in healthy renal tissue ranged from 0 to 2 (average 0.9), as well as in renal clear cell carcinoma (average 1.1). Seven of 20 (35%) healthy tissue samples failed to stain with BMP-6 antibody, compared to 2/20 (10%) tumor samples (p < 0.05). BMP-6 immunostaining was positive in 18/20 CCRC samples. Staining was localized in the cytoplasm and/or membrane of malignant cells. Malignant tissue had significantly higher BMP-6 mRNA expression than healthy tissue. There was no significant correlation between BMP-6 mRNA and protein expression with disease presentation, disease progression and patients’ characteristics. Long-term follow-up of our patients is needed to determine the possible role of increased expression of BMP-6 in CCRC.

Bone morphogenetic protein-7 expression is down-regulated in human clear cell renal carcinoma

BACKGROUND Recent studies demonstrated that the expression pattern of bone morphogenetic protein-7 (BMP-7) is altered in different tumors. We determined expression of BMP-7 in human clear cell renal carcinoma (CCRC). METHODS Samples from cancer and corresponding healthy tissue were obtained from 20 patients who underwent nephrectomy for CCRC. Expression of BMP-7 mRNA was determined by reverse transcriptase polymerase chain reaction (RT-PCR), and protein expression was analyzed by immunohistochemistry. RESULTS RT-PCR showed strong down-regulation of BMP-7 mRNA in cancer tissue. Immunohistochemistry revealed expression of BMP-7 in normal renal tissue, with almost complete loss of BMP-7 expression in malignant cells of 6 patients (30%). After 3 years of follow-up, 5 out of 6 patients with high BMP-7 mRNA expression were alive and disease-free, compared with 9 out of 14 patients with low BMP-7 mRNA expression. CONCLUSIONS BMP-7 mRNA and protein expression were down-regulated in CCRC. Further prospective studies are needed to characterize the role of BMP-7 in human CCRC.

Lupus nephritis in Croatian children: clinicopathologic findings and outcome

We report clinical and histopathological features, treatment and outcome of 37 Croatian children with biopsy-proven lupus nephritis seen over a 30-year period. The mean age at lupus nephritis presentation was 12.11 ± 2.59 years (range 4.66–17.0). The most frequent histopathological finding was class IV (37.8%), followed by class III (35.1%), class V (16.2 %) and class II (10.8 %) lupus nephritis. Compared with other classes there were more boys among patients with class IV lupus nephritis, and hypertension, nephrotic syndrome and decreased estimated glomerular filtration rate at presentation were more common. The median histopathological activity and total scores were highest in class IV lupus nephritis patients. The mean follow-up was 7.14 ± 4.71 years, ranging from 1.1 years to 21.0 years. Kaplan–Meier estimates of patient and kidney (without renal failure) survival rates were 90.5% and 87 % at five years. The renal survival rate of class IV lupus nephritis patients was found significantly lower compared with other histological classes combined. Decreased estimated glomerular filtration rate at the time of diagnosis, class IV lupus nephritis versus other lupus nephritis classes, and high total histological score were the parameters significantly associated with adverse outcome. The therapy with cyclophosphamide showed as superior to the therapy with azathioprine.

Fibronectin glomerulopathy in a 34-year-old man: a case report.

Fibronectin glomerulopathy is an inherited non-imune-mediated glomerulopathy associated with the massive deposition of fibronectin. It presents with proteinuria, microscopic hematuria, and hypertension that lead to end-stage renal failure in the second to sixth decade of life. A 34-year-old male was referred with proteinuria (6 g/day), microscopic hematuria and hypertension (220/130 mmHg). Renal biopsy specimen showed massive deposits of fibronectin in the mesangium and subendothelial spaces. After 20 months of multidrug treatment his renal function is stable.