Regenerative stimulus increases hepatocyte tight junctional permeability.

Experience with young animals, animals administered certain hepatotoxins and animals with two-thirds hepatectomy suggests that tight junctional permeability is increased in states characterized by architectural remodeling in the liver. In this work we correlate changes in tight junctional morphometry induced by two-thirds hepatectomy with changes in biliary permeability assessed by sucrose and horseradish peroxidase permeation and by alterations in biliary outputs of anionic and cationic cholephilic probes. By freeze-fracture examination tight junctional strand counts, density and orientation parallel to canaliculi were all reduced 24 hr after two-thirds hepatectomy. Occasionally, strands were perpendicular to the canaliculi, creating an unobstructed communication between bile and intercellular spaces. These morphological changes correlated with increased sucrose and paracellular horseradish peroxidase access into bile, with reduced biliary outputs of low molecular weight and especially with cationic cholephilic probes. The data support an increased but still charge-selective permeability of the biliary tree, which was induced by two-thirds hepatectomy 24 hr before. Presumably, fixed intercellular connections (tight junctions and gap junctions) must be loosened or lysed to allow the architectural reorganization required by the hepatocellular regenerative process.

Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features.

BACKGROUND AND METHODS: We describe a new form of hepatitis, occurring in 10 patients over a period of six years, characterized clinically by manifestations of severe hepatitis, histologically by large syncytial giant hepatocytes, and ultrastructurally by intracytoplasmic structures consistent with paramyxoviral nucleocapsids. RESULTS: The patients ranged in age from 5 months to 41 years. The tentative clinical diagnosis before biopsy was non-A, non-B hepatitis in five patients and autoimmune chronic active hepatitis in the others. Five patients underwent liver transplantation; the others died. The diagnosis of syncytial giant-cell hepatitis was established pathologically. The liver cords were replaced in all 10 patients by syncytial giant cells with up to 30 nuclei. In 8 of the 10 the cytoplasm contained pleomorphic particles of 150 to 250 microns, filamentous strands, and particles of 14 to 17 nm with peripherally disposed spikes resembling paramyxoviral nucleocapsids. Structures resembling degenerated forms were found in the other two patients. One of two chimpanzees injected with a liver homogenate from the index patient had an increase in the titer of paramyxoviral antibodies, probably an anamnestic reaction to previous paramyxoviral infection, suggesting that a paramyxoviral antigen but not viable virus was present in the liver homogenate. CONCLUSIONS: Although further virologic studies will be required for precise classification, we believe that paramyxoviruses should be considered in patients with severe sporadic hepatitis.

Interstitial foam cells in renal biopsies: an aid in differentiating idiopathic membranoproliferative glomerulonephritis (type I) and membranoproliferative glomerulonephritis associated with systemic lupus erythematosus.

A patient with nephrotic syndrome whose renal biopsy showed membranoproliferative glomerulonephritis (MPGN) is described. Clinical and laboratory findings included an erythematous malar flush, proteinuria, casts in the urine and a positive antinuclear factor. Hence, it was not clear whether the MPGN was idiopathic, secondary to early systemic lupus erythematosus (SLE) or mainly a renal form of SLE. Treatment with prednisone and azathioprine was unsuccessful, and no new clinical or serological features of SLE appeared. A second renal biopsy 19 months later showed MPGN and large numbers of interstitial foam cells. The finding of foam cells prompted a review of other renal biopsies which were diagnosed as MPGN type I and diffuse proliferative lupus nephritis (DPLN), including lupus-associated MPGN. Nine of thirty-eight (24%) MPGN type I but none of 22 DPLN biopsies contained interstitial foam cells. Therefore, finding foam cells in a renal biopsy may help in differentiating MPGN type I from lupus-associated MPGN.

Naproxen-associated renal failure in a child with arthritis and inflammatory bowel disease.

Renal failure occurred in a 14-year-old girl with peripheral arthritis associated with inflammatory bowel disease while she was being treated with naproxen. She had previously received aspirin and tolmetin sodium and had no complications. A renal biopsy showed a severe tubulointerstitial nephritis. Although her renal function improved somewhat with corticosteroid treatment, it worsened when the steroids were discontinued. This case emphasizes that renal failure can develop insidiously in children on nonsteroidal anti-inflammatory drug therapy and that such children must be monitored closely for signs of nephrotoxicity.

Clinical significance of renal biopsies showing mixed mesangial and global proliferative lupus nephritis.

Renal biopsies of 70 children with systemic lupus erythematosus were categorized, according to the World Health Organization classification, as normal (five, 7%), mesangial (23, 33%), focal segmental proliferative (11, 16%), diffuse global proliferative (20, 29%) (ie, greater than or equal to 80% of glomeruli showing mesangioendothelial cell proliferation and/or deposition of immune complexes along the subendothelial margin of glomerular capillaries), and membranous (six, 8%) lupus nephritis (LN). In addition, five (7%) biopsies showed global proliferative LN in less than 80% of glomeruli and mesangial LN in the others. We assessed the renal status of these five patients at the time of renal biopsy and at outcome following prednisone treatment, with or without azathioprine. Four patients improved and later had either a normal urinalysis or only trace proteinuria. A low chronicity index was calculated on the biopsies of these patients. The fifth patient, whose condition did not improve, demonstrated a high chronicity index on renal biopsy. Overall, the renal status at outcome in the patients showing mixed mesangial and global proliferative LN more closely resembled that of patients with mesangial than diffuse global proliferative LN.

Cholestasis: surgical pathology, mechanisms, and new concepts.

This report has attempted to describe concisely the main diagnostic morphological features seen in cholestasis and to explain them mechanistically. The number of clinical conditions in which cholestasis can be found is extremely large and varied, so that no single mechanism explains all cases; in fact, multiple factors are operative in frequent instances. Currently used terminology and concepts are explained. The report is not intended to be comprehensive but is intended to deal with the most common types of cholestasis and with those in which recent advances in new knowledge have been made. The first step, in all cases, is to try to localize the site of obstruction, so an anatomic classification of cholestasis is offered as being most helpful, both in diagnostic work and in consideration of the mechanisms involved. In selecting the cases for special consideration, a personal bias is introduced but is unavoidable. The discussion of canalicular cholestasis is particularly abridged because many of the mechanisms proposed, including the two that are briefly discussed, are still the subject of ongoing investigation but are included because they are illustrative of current concepts in the field.

IgA nephropathy: Henoch-Schönlein purpura and Berger's disease in one patient.

A patient is described who had an attack of Henoch-Schönlein purpura with no renal dysfunction at 4 years of age. She recovered with conservative management. There were no further episodes of Henoch-Schönlein purpura and her urinalysis remained normal for the next 11 years. At age 15, she developed repeated bouts of gross hematuria and proteinuria, and a renal biopsy was performed 3 years later. Light microscopy showed mesangial proliferative glomerulonephritis with granular, mesangial deposits of IgA by immunofluorescence and numerous, electron-dense deposits in mesangial regions by electron microscopy. These findings were consistent with a diagnosis of Berger's disease. The occurrence of Henoch-Schönlein purpura at 4 years and Berger's disease at 15 years in the same patient suggests that these two conditions are related.

Prognostic significance of urinary findings and renal biopsies in children with Henoch-Schönlein nephritis.

Clinical course and renal biopsy were evaluated as predictors of renal outcome in 21 children with Henoch-Schönlein nephritis. Persisting heavy proteinuria and severe glomerular changes most accurately predicted those patients who were likely to develop renal failure. Renal biopsy is recommended only in patients with a nephrotic or nephritic/nephrotic picture.

Membranoproliferative glomerulonephritis type I in children: correlation of clinical features with pathologic subtypes.

Renal biopsies from 33 patients with membranoproliferative glomerulonephritis (MPGN) type I were reviewed to identify pathologic subtypes of this disease and assess their correlation to clinical features. The patients were divided into two groups: group A included 16 patients in chronic or end-stage renal failure and group B 17 patients with no evidence of renal insufficiency. At presentation, a nephrotic or nephritic syndrome and azotemia were equally common in both groups. The incidence of hypertension was significantly increased in group A (P less than 0.05), while recurrent gross hematuria was more common in group B. Nephrotic syndrome was more common during the course of illness in group A. Three subtypes of MPGN type I were recognized, based on whether duplication of glomerular capillary basement membranes was focal segmental (FS; 9 cases), diffuse global (DG; 18 cases), or mixed segmental and global (6 cases). Eight of nine patients showing FS MPGN type I were in group B (p less than 0.05). In contrast, 11 of 18 patients with DG MPGN type I and 4 of 6 with a segmental and global pattern were in group A (P = not significant). Therefore, FS MPGN is a good predictor of a favorable clinical outcome, whereas the other two subtypes are not. This was confirmed by a 100% actuarial kidney survival for the nine patients with FS MPGN and a 50% kidney survival of 7.5 years for patients with the other two subtypes.

Determination of circulating immune complexes, C3 and C4 complement components and anti-DNA antibody in different classes of lupus nephritis.

Circulating immune complexes (CIC) were measured in 237 sera from children who underwent a renal biopsy during the course of systemic lupus erythematosus. CIC-positive sera contained a lower mean level of C3 but not C4. Anti-DNA antibody was similar in CIC-positive and negative sera. The World Health Organization classification of lupus nephritis was used to categorize the biopsies. CIC, C3, C4 and anti-DNA antibody were determined to assess whether they correlated with the severity of renal lesions. Of 25 sera obtained at renal biopsy from patients with classes 2, 3 and 4, 16 were positive for CIC. C3 was significantly lower in classes 3 and 4 than in class 2. C4 was reduced and anti-DNA antibody was present in classes 2, 3 and 4. Determination of the level of C3 but not C4, CIC or anti-DNA antibody correlates with the severity of lupus nephritis seen on renal biopsies. Nevertheless, performance of a renal biopsy is preferred.

The significance of focal segmental glomerulosclerosis in oligomeganephronia.

Oligomeganephronia (OMN) is characterized by a reduced number of nephrons, with compensatory hypertrophy of the remaining glomeruli and tubules. The clinico-pathological features of six cases seen at The Hospital for Sick Children, Toronto were reviewed. One patient presented in infancy (10 days of age), the others between 12.8 and 14.5 years (mean 13.7 years), with long-standing polydipsia and polyuria, enuresis, and growth retardation. All patients had proteinuria which tended to increase as the disease progressed. At renal biopsy, four patients showed significant proteinuria (greater than 1.3 g/24 hr). Biopsies from these patients showed focal segmental glomerulosclerosis (FSGS) and all have rapidly progressed to dialysis/transplantation. The two remaining patients had lesser degrees of proteinuria (less than 0.3 g/24 hr) and no evidence of FSGS on biopsy; however, they are currently in chronic renal failure (mean serum creatinine 2.8 mg/dl). We conclude that increasing proteinuria in patients with OMN heralds the development of FSGS, presumably due to functional overload of the reduced nephron number. This is associated with a rapid decline in renal function.

Amiodarone-associated phospholipidosis and fibrosis of the liver. Light, immunohistochemical, and electron microscopic studies.

The hepatic morphological findings in 3 patients treated with amiodarone, a potent and effective antiarrhythmic drug, are reported. An enlarged liver and mild elevation of hepatic enzymes were the most important clinical findings. Fibrosis, cholangitis, mixed inflammatory infiltrate, and cytoplasmic granularity of the hepatocytes were the main histologic changes common to all cases. In 2 of the cases the presence of Mallory bodies was confirmed by electron microscopy. In 1 of these 2 cases, Mallory bodies were also confirmed by immunostaining. Ultrastructurally, numerous cytoplasmic inclusions with a membranous or lamellar structure identical to those described in phospholipidosis were the most striking features seen in hepatocytes, biliary epithelial cells, Kupffer cells, and endothelial cells.

Clinical features and glomerular immunofluorescence of renal biopsies from children with nephrotic syndrome due to minimal change disease and two variants of mesangial proliferative glomerulonephritis.

Response to initial course of prednisone and clinical outcome were reviewed in 82 children with nephrotic syndrome (NS) due to minimal change disease (MCD) and 2 variants of mesangial proliferative glomerulonephritis (MesPGN). Renal biopsies in Type I MesPGN showed only increased mesangial cells and matrix, whereas those in Type II MesPGN also showed interstitial fibrosis, tubular atrophy, global glomerulosclerosis and hyalinosis. Response to prednisone was complete in most cases (95% in MCD, 82% in Type I and 72% in Type II MesPGN). Remission of NS for more than 1 year while off prednisone occurred in 91% of patients with Type I MesPGN and 49% with MCD, but in only 14% with Type II MesPGN. The influence of immunoglobulins +/- complement in mesangial regions of glomeruli on initial response and outcome was assessed. Response to prednisone and outcome did not differ in IMF-positive and -negative MCD or in Type I and Type II MesPGN.

Incidence and prognostic importance of glomerular crescents in renal diseases of childhood.

The renal biopsies of 372 children with various glomerular disorders were reviewed and crescent formation was seen in 56 cases (15%). Four disorders, i.e. systemic lupus erythematosus, membranoproliferative glomerulonephritis (MPGN) types I and II and Henoch-Schönlein disease accounted for 74% of 10 diagnostic categories. Idiopathic rapidly progressive glomerulonephritis (RPGN) was seen in only 2 cases. Crescents associated with MPGN types I or II or idiopathic RPGN had a bad renal prognosis, whereas the presence of crescents in other disorders did not necessarily affect the renal outcome. Immunofluorescent and electron microscopic findings are essential to distinguish many conditions which may be associated with crescent formation in childhood renal disease.

Characteristics of a benign subtype of dense deposit disease: comparison with the progressive form of this disease.

Pathologic, clinical and serum complement studies were performed on 18 patients with dense deposit disease (DDD). The patients were divided into 3 groups: group A (10 patients who developed end-stage renal failure within 2.9 +/- 1.0 years of onset) group B (3 patients who developed elevated serum creatinines within 6.8 +/- 4.8 years of onset) and group C (5 patients with no evidence of renal insufficiency after 11.0 +/- 1.4 years of follow-up). Renal biopsies from all patients showed intramembranous, electron-dense deposits in glomerular capillary basement membranes. Most group A and B patients presented with a nephritic and/or nephrotic syndrome and followed an active clinical course. In contrast, group C patients presented with either a nephrotic syndrome or asymptomatic proteinuria +/- hematuria and followed a benign course. Sera from group A and B patients contained reduced concentrations of C3 and factor B and large amounts of C3 nephritic factor (NeF) activity. In contrast, serum of group C patients contained normal amounts of C3 and factor B and low levels of C3 NeF activity. These studies show that some patients with DDD (group C) have a benign illness and that they can be identified by serum levels of C3, factor B and C3 NeF activity.

Idiopathic membranous glomerulopathy in Canadian children: a clinicopathologic study.

The 1,205 renal biopsies performed at The Hospital for Sick Children, Toronto, were reviewed to identify membranous glomerulopathy. Fourteen patients had a clinicopathologic diagnosis of idiopathic membranous glomerulopathy. Typical thickening of glomerular capillary basement membranes, a spike-and-dome pattern, and subepithelial electron-dense deposits were noted. Strong deposits of IgG and weaker deposits of C3, IgM, and IgA were present in glomeruli. Stages of membranous glomerulopathy on electron microscopy were I in one biopsy, II in nine biopsies, and III in four biopsies. Two additional biopsies from one child initially showed minimal lesion-type disease; later, a third showed membranous glomerulopathy. At presentation 11 patients had nephrotic syndrome, seven had hypertension, and eight had hematuria. Now four are in remission, seven have active disease with normal renal function, and three have renal failure. Patients with hypertension tended to do worse than those without. Age at onset, presence of nephrotic syndrome or hematuria, and administration of steroids or immunosuppressive drugs did not adversely affect outcome. Furthermore, clinical outcome did not correlate with stage of disease. Hence pathologic and most clinical features do not predict long-term prognosis in children with membranous glomerulopathy.

Focal segmental glomerulosclerosis with idiopathic nephrotic syndrome: three types of clinical response.

In a retrospective analysis, 51 patients with focal segmental glomerulosclerosis and idiopathic nephrotic syndrome, who were treated with steroid or cyclophosphamide therapy, were divided into three clinical groups according to the remission profile of their nephrotic syndrome. Group 1 patients (19.37%) consistently responded to medication; none has progressive renal failure (mean follow-up 10.6 years). Group 2 patients (25, 40%) failed to respond to medication; terminal renal failure has occurred in 12 of them. Group 3 patients (7, 14%) initially appeared to be responsive to medication and continued to respond for up to 18 months, but subsequently became unresponsive to any therapy; five of them have required dialysis or transplantation. This third group of patients could not be separated clinically or pathologically from group 1 patients, all of whom have an excellent prognosis. One should, therefore, be cautious about predicting the outcome of steroid-responsive nephrotic patients, especially those with FSGS, until at least 18 months after the onset of illness.

Modern aspects of the morphology of viral hepatitis.

The morphologic pathology of human viral hepatitis and its sequelae are reviewed in this article. Emphasis is placed on new information, including the current status of the pathologic diagnosis of hepatitis non-A, non-B. The article includes a discussion of aspects of the virology that are pertinent to an understanding of the significance of viral markers in the liver. A small contribution of the authors is a brief description of the neocholangiole, a duct of Hering-like structure seen following hepatic necrosis from many causes, including the severe forms of viral hepatitis.