Intralobular Fibrosis Research Articles

Chronic pancreatitis and inflammatory bowel disease: true or coincidental association?

OBJECTIVE: Several cases of pancreatitis have been described during the course of Crohn’s disease (CD) or ulcerative colitis (UC), but many of them were related to either biliary lithiasis or drug intake. We tried to evaluate the clinical and morphological features of so-called idiopathic pancreatitis associated with inflammatory bowel disease and to define their pathological characteristics. METHODS: Chronic idiopathic pancreatitis was diagnosed on the basis of abnormal pancreatograms suggestive of chronic pancreatitis associated with or without impaired exocrine pancreatic function, or pathological examination in patients undergoing pancreatic resection. We found 6 patients presenting with features of chronic idiopathic pancreatitis and UC and 2 patients with CD seen between 1981 and 1996 in three hospital centers of the south of France. A review of the literature has identified 6 cases of pancreatitis associated with UC and 14 cases of pancreatitis associated with CD based on the above criteria. RESULTS: Hyperamylasemia was not a sensitive test since it was present in 44% and 64% of patients with UC or CD. In UC, pancreatitis was a prior manifestation in 58% of patients. In contrast, the pancreatitis appeared after the onset of CD in 56% of the cases. In patients with UC, pancreatitis were associated with severe disease revealed by pancolitis (42%) and subsequent surgery. Bile duct involvement was more frequent in patients with UC than with CD (58% vs 12%) mostly in the absence of sclerosing cholangitis (16% vs 6%). Weight loss and pancreatic duct stenosis were also more frequent in UC than in CD (41% vs 12% and 50% vs 23%, respectively). Pathological specimens were analyzed in 5 patients and demonstrated the presence of inter- and intralobular fibrosis with marked acinar regression in 3 and the presence of granulomas in 2 patients, both with CD. CONCLUSIONS: Pancreatitis is a rare extraintestinal manifestation of inflammatory bowel disease. Chronic pancreatitis associated with UC differs from that observed in CD by the presence of more frequent bile duct involvement, weight loss, and pancreatic duct stenosis, possibly giving a pseudo-tumor pattern.

Genotypes of alcohol-metabolizing enzymes in relation to alcoholic chronic pancreatitis in Japan.

Long-term consumption of large amounts of alcohol is the main cause of chronic pancreatitis. All heavy drinkers, however, do not contract chronic pancreatitis. Although genetic predisposition to alcoholism and alcoholic liver disease has been reported, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine the relation between genotypes of alcohol-metabolizing enzymes and chronic alcoholic pancreatitis, we examined genotype patterns of aldehyde dehydrogenase 2 (ALDH 2), alcohol dehydrogenase 2 (ADH 2) and cytochrome P-4502E1 (CYP2E1) in 54 patients with chronic alcoholic pancreatitis who were diagnosed in general hospitals in all over Japan and compared with those in 30 patients with chronic nonalcoholic pancreatitis or in 46 alcoholics with normal pancreatic function. There were no significant differences in the distribution of genotypes of ALDH 2 and CYP2E1 among those three groups. As for the ADH 2 genotype, distribution of 2(1)/2(1), 2(1)/2(2), and 2(2)/2(2) was 35%, 30%, and 35% in alcoholics with normal pancreatic function; 4%, 39%, and 57% in the chronic alcoholic pancreatitis group; and 0%, 50%, and 50% in the chronic nonalcoholic pancreatitis group, respectively. The frequency of ADH 2(2) allele was significantly higher in the chronic alcoholic pancreatitis group, compared with alcoholics with normal pancreatic function; but, it was not significantly different from that in the chronic nonalcoholic pancreatitis group. We also examined the relation between pancreatic fibrosis or pancreatitis histologically diagnosed and genotypes of alcohol-metabolizing enzymes in alcoholic autopsy cases. Twenty of 31 cases showed moderate or severe pancreatic fibrosis and showed intralobular + interlobular fibrosis, which is characteristic in alcoholic pancreatitis or intralobular fibrosis. ADH 2(2) allele tended to show a high frequency in the intralobular + interlobular fibrosis group, compared with that in the intralobular fibrosis group (75.0% vs. 41.7%, p < 0.1). The chronic pancreatitis group had a significantly higher frequency of the ADH 2(2) allele than that in cases without such findings (87.5% vs. 58.7%, p < 0.05). However, the ALDH 2 and CYP2E1 genotypes showed no significant relation to the findings of pancreatic fibrosis or histological pancreatitis. These data suggest that the risk of chronic alcoholic pancreatitis diagnosed clinically and pathologically seems to be associated with the ADH 2(2) allele in the genotypes of alcohol-metabolizing enzymes.

Intoxicação experimental por sementes de Crotalaria spectabilis (Leguminosae) em suínos

Para estudar os efeitos da ingestão de sementes de Crotalaria spectabilis em suínos, 14 porcos foram divididos em 5 grupos; quatro (A-D) eram formados por 3 porcos e um (Grupo E) por dois porcos. Com exceção do grupo A, que serviu como controle, os porcos foram alimentados com ração contendo 0,3 e 0,5% (Grupos B e C) e 1% (Grupos D e E) de sementes moídas de C. spectabilis por 32 (Grupo D), 44 (Grupo E) e 120 (Grupo B e C) dias. Um suíno do Grupo D e 2 suínos do Grupo B, morreram 8, 70 e 137 dias após o início do experimento; os restantes 11 suínos foram sacrificados em períodos que variaram entre 52 e 159 dias após o início do experimento. Dez dos 11 suínos tratados apresentaram perda do apetite e subdesenvolvimento. Outros sinais clínicos observados foram depressão, perda localizada de pêlos e distúrbios respiratórios. As principais lesões ocorreram no fígado. Em um caso eram agudas e consistiam principalmente de padrão lobular acentuado resultante de necrose centrolobulara massiva. Os outros 11 suínos apresentavam lesões hepáticas crônicas; o fígado estava firme, com cápsula espessada e aderências fibrosas entre os lobos e a estruturas adjacentes. Microscopicamente havia fibrose capsular, interlobar, interlobular e intralobular; hepatomegalocitose e proliferação de ductos biliares. Bilestase foi observadada no fígado de dois suínos; num outro havia regeneração hepatocelular nodular. Os pulmões de 4 suínos estavam avermelhados e firmes. Histologicamente havia espessamento dos septos interalveolares e interlobulares por edema, fibrose e infiltração celular, e proliferação de pneumócitos tipo II. Alterações renais foram observadas apenas microscopicamente e incluíam, principalmente, hepatomegalocitose das células epiteliais tubulares. Em 6 porcos observaram-se edemas cavitários (ascite, hidrotórax e hidropericárdio) de intensidade discreta a moderada. Alterações vasculares microscópicas consistindo de espessamento e hialinização da parede arterial foram observadas no pulmão de 5 suínos e no rim de 3. Quatro suínos tinham alterações sugestivas de encefalopatia hepática. Essas alterações não foram observadas nos suínos controles.

Genotypes of Alcohol‐Metabolizing Enzymes and the Risk for Alcoholic Chronic Pancreatitis in Japanese Alcoholics

Genetic predisposition to alcoholism and alcoholic liver disease has been reported. However, genetic susceptibility to alcoholic pancreatitis is still a matter of debate. To determine it, we examined genotype patterns of aldehyde dehydrogenase (ALDH2), alcohol dehydrogenase (ADH2 and ADH3), and cytochrome P-4502E1 (CYP2E1) in alcoholic pancreatitis patients. In 296 alcoholic patients, 52 cases showed findings of chronic pancreatitis by ultrasonography and x-ray computed tomography and/or had a history of pancreatitis (P+). The remaining 244 patients had neither abnormal findings of the image examinations nor a history of pancreatitis (P-). As for the ADH2 genotype, distribution of 2(1)/2(1), 2(1)/2(2), and 2(2)/2(2) was 22, 37, and 42% in P+ patients, whereas 34, 35, and 30% in P- patients, respectively. The frequency of ADH2(2)/2(2) genotype was significantly higher in P+ patients, compared with that in P- patients. There were no significant differences in the distribution of ADH3, ALDH2, and CYP2E1 genotypes between P+ and P- patients. In 14 alcoholic patients who showed low contents of fecal chymotrypsin, which suggests dysfunction of pancreatic exocrine, the rate of ADH2(2)/2(2) genotype also tended to be higher (50%) than in 74 controls who showed normal contents of the fecal chymotrypsin (28%). No differences were observed in genotypes of ADH3, ALDH2, and CYP2E1. Moreover, the frequency of ADH2(2)/2(2) genotype was significantly higher in autopsy cases with interlobular fibrosis in the pancreas, which suggests alcoholic pancreatic damage, than in cases with only intralobular pancreatic fibrosis. These data suggest that the risk of alcoholic pancreatitis seems to be associated with the presence of ADH2(2)/2(2) genotype.

Histological assessment of chronic pancreatitis at necropsy.

To evaluate the histological criteria used to diagnose chronic pancreatitis; and to assess interobserver variation among general pathologists. Forty five cases of chronic pancreatitis diagnosed in necropsy were reviewed to determine whether the diagnosis was acceptable retrospectively. These cases were diagnosed initially as chronic pancreatitis in the final necropsy report complied by general pathologists. In reviewing these cases, special attention was paid to irregular fibrosis and destruction of the lobular architecture. The 45 cases were re-assigned to seven different diagnostic categories: chronic pancreatitis, 21 (47%) cases; interstitial fibrosis with or without chronic inflammation, 11 (24%) cases; repair stage of acute pancreatitis, four (9%) cases; severe fatty infiltration, three (7%) cases; chronic inflammation without interstitial fibrosis, two (4%) cases; haemochromatosis, one (2%) case; and undetermined, three (7%) cases. The histological spectrum of chronic pancreatitis was very wide and it was often misdiagnosed. Acinar atrophy, acinar dilation and intralobular fibrosis were diagnostic of chronic pancreatitis. Differential diagnoses include the repair stage of acute pancreatitis, severe fatty infiltration and haemochromatosis. Recognition of these findings may help to reduce overdiagnosis of chronic pancreatitis.

Morphological identification of and collagen synthesis by periacinar fibroblastoid cells cultured from isolated rat pancreatic acini.

Rat pancreatic periacinar fibroblastoid cells (PFCs) appear to be involved in intralobular fibrosis and acinar cell regeneration. We isolated pancreatic acini of the rat, cultured the fibroblastoid cells, and characterized the cells morphologically and immunohistochemically. Isolated acini were seeded on culture dishes, and spindle-shaped cells migrated and proliferated. On Electronmicroscopic examination, microfilament bundles were seen, and the intracellular localization of vimentin, alpha-smooth muscle actin, and non-muscle myosin was identified immunohistochemically. These findings strongly suggest that the cells were myofibroblast-like. The PFCs were also demonstrated, immunohistochemically, to contain prolyl hydroxylase, type-I procollagen, type-III procollagen, type-IV collagen, fibronectin, and laminin. Stimulation by transforming growth factor beta 1 (TGF beta 1) increased intracellular immunoreactive prolyl hydroxylase and collagen synthesis in the PFCs. These findings indicate that PFCs proliferate in culture as myofibroblast-like cells and synthesize extracellular matrix components. It is possible that PFCs are involved in intralobular fibrosis in response to stimulation with TGF beta 1.

Course of alcoholic chronic pancreatitis: A prospective clinicomorphological long-term study

BACKGROUND & AIMS: The pathogenesis of alcoholic chronic pancreatitis and its relationship to alcoholic acute pancreatitis are debated. According to our recent clinical long-term study, alcoholic chronic pancreatitis seems to evolve from severe acute pancreatits. The aim of this study was to correlate clinical findings to the pancreatic histopathology at early and advanced stages of the disease. METHODS: Morphological changes (pseudocysts, autodigestive necrosis, calcification, and perilobular and intralobular fibrosis) were recorded in 37 surgical and 46 postmortem pancreas specimens of 73 patients from our long-term series, who progressed from clinically acute to chronic pancreatitis (mean follow-up, 12 years). Pancreatic function was monitored at yearly intervals. RESULTS: Surgical interventions were performed at a mean of 4.1 years from onset. Histologically, focal necrosis (49%) and mild perilobular fibrosis (54%) predominated, Pseudocysts (n = 41, mostly postnecrotic) occurred in 88% within 6 years from onset. Autopsy specimens were obtained at a mean of 12 years. These pancreata often showed severe perilobular and intralobular fibrosis (85%) and calcifications (74%), but rarely necrosis (4%). Fibrosis correlated with progressive pancreatic dysfunction (P < 0.001), particularly in the 10 patients with two histological assessments (mean interval between biopsy and autopsy, 8 years). CONCLUSIONS: The data support an evolution from severe alcoholic acute pancreatitis to chronic pancreatitis. (Gastroenterology 1996 Jul;111(1):224-31)

Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology.

Non-cirrhotic, long-standing portal hypertension of unknown aetiology is being re-evaluated histopathologically and clinically. In this study, we examined 107 livers with this condition (92 wedge biopsy and 15 autopsy specimens) from five institutions in Japan. These cases were histologically categorized into four groups: idiopathic portal hypertension (66 cases), nodular regenerative hyperplasia (14 cases), partial nodular transformation (two cases), and incomplete septal cirrhosis (25 cases). These four groups shared several histological features: dense portal fibrosis with portal venous obliteration and intralobular slender fibrosis. In addition, the histopathological features characteristic of one group were also found to a mild degree in other groups. The histopathological lesions preceding portal venous obliteration remain speculative. However, the portal venous obliteration may be responsible for the occurrence of sustained portal hypertension and several of the pathological changes in these livers. It seems likely that idiopathic portal hypertension, nodular regenerative hyperplasia, partial nodular transformation and incomplete septal cirrhosis comprise a family of non-cirrhotic, long-standing portal hypertension in Japan, and the histological differences between them may reflect chronological progression of a single disease.

Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice

BACKGROUND & AIMS: Transforming growth factor beta (TGF-beta) is a putative mediator of fibrosis in several chronic diseases. Recently, chronic pancreatitis was suggested to be related to acute pancreatitis in the so-called necrosis-fibrosis sequence hypothesis. The present study investigated whether TGF-beta is able to promote chronic fibrosis after repeated courses of necrotizing acute pancreatitis induced by cerulein in mice. METHODS: Six episodes of acute pancreatitis were repeatedly induced at weekly intervals in mice receiving either recombinant TGF-beta (4 micrograms in 4 days) or excipient alone at each induction. One week after the last induction, pancreatic lesions and collagen deposition were histologically assessed. Expression of pancreatic fibronectin messenger RNA was also examined in both groups. RESULTS: TGF-beta had no influence on a single course of acute pancreatitis. After six courses of acute pancreatitis, only mild inflammatory changes were observed in the control group. In contrast, important areas of perilobular and intralobular fibrosis were observed adjacent to inflammatory and necrotic foci in the TGF-beta group. Fibronectin messenger RNA expression was significantly higher in this group. CONCLUSIONS: TGF-beta promotes development of pancreatic fibrosis after recurrent episodes of acute pancreatitis. This model of pancreatic fibrosis could be used as a model of chronic pancreatitis consistent with the necrosis-fibrosis sequence hypothesis. (Gastroenterology 1996 Feb;110(2):576-82)

Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease

The pathogenesis of alcohol-induced liver disease involves the adverse effects of ethanol metabolites and oxidative tissue injury. Previous studies indicated that covalent protein adducts with reactive aldehydes may be formed in alcohol consumers. To study the role of such protein adducts in the development of liver injury, we examined the sequential appearances of adducts of the ethanol metabolite acetaldehyde (AA) and of two products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenol (HNE), in ethanol-fed micropigs. Immunohistochemical stainings using specific antibodies that recognize epitopes of each adduct were performed from liver biopsy specimens obtained at 1, 5, and 12 months from micropigs fed either control diet (n = 5) or ethanol-containing diets (n = 5). After 1 month on the ethanol diet, AA and MDA adducts were observed primarily in the perivenous regions co-localizing with each other and coinciding with increased concentrations of serum aminotransferase markers of liver injury. HNE adducts were usually less intense and more diffuse, and were also seen in some biopsy specimens from control animals. Although the most intense staining reactions at 5 months remained in zone 3, a more widespread distribution was usually seen together with increased evidence of steatonecrosis and focal inflammation. In terminal biopsies at 12 months, perivenous fibrosis was present in three of five biopsy specimens. More extensive pericentral and intralobular fibrosis was noted in one micropig fed ethanol for 21 months. These studies demonstrate that covalent adducts of proteins with reactive aldehydes are formed in early phases of alcoholinduced liver disease. Perivenous adducts of the AA product of ethanol metabolism and the MDA product of lipid peroxidation appear to precede necrosis and fibrosis.

Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease

The pathogenesis of alcohol-induced liver disease involves the adverse effects of ethanol metabolites and oxidative tissue injury. Previous studies indicated that covalent protein adducts with reactive aldehydes may be formed in alcohol consumers. To study the role of such protein adducts in the development of liver injury, we examined the sequential appearances of adducts of the ethanol metabolite acetaldehyde (AA) and of two products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenol (HNE), in ethanol-fed micropigs. Immunohistochemical stainings using specific antibodies that recognize epitopes of each adduct were performed from liver biopsy specimens obtained at 1, 5, and 12 months from micropigs fed either control diet (n = 5) or ethanol-containing diets (n = 5). After 1 month on the ethanol diet, AA and MDA adducts were observed primarily in the perivenous regions co-localizing with each other and coinciding with increased concentrations of serum aminotransferase markers of liver injury. HNE adducts were usually less intense and more diffuse, and were also seen in some biopsy specimens from control animals. Although the most intense staining reactions at 5 months remained in zone 3, a more widespread distribution was usually seen together with increased evidence of steatonecrosis and focal inflammation. In terminal biopsies at 12 months, perivenous fibrosis was present in three of five biopsy specimens. More extensive pericentral and intralobular fibrosis was noted in one micropig fed ethanol for 21 months. These studies demonstrate that covalent adducts of proteins with reactive aldehydes are formed in early phases of alcohol-induced liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Fatal Hepatotoxicity Following Oral Administration of Amiodarone

To report a case of fatal hepatotoxicity associated with the chronic use of oral amiodarone. Long-term administration of amiodarone for the control of intractable ventricular tachycardia was associated with fatal hepatotoxicity in a patient receiving amiodarone for 14 months. Although most hepatic adverse effects associated with amiodarone are transient and reversible with time, deaths resulting from amiodarone-induced hepatotoxicity have been reported. The relation of hepatotoxicity to cumulative dose and duration of therapy is debated. The histopathologic features of amiodarone-induced hepatotoxicity include Mallory bodies, steatosis, intralobular inflammatory infiltrates, fibrosis, and phospholipidosis. Evidence pertaining to both mild and severe amiodarone toxicity indicates that cumulative dose may correlate with overall toxicity and, therefore, maintenance doses should be kept as low as possible. Patients should be followed with monitoring of liver function test results every 3-6 months.

Influence of human immunodeficiency virus infection on hepatitis delta virus superinfection in chronic HBsAg carriers.

It is generally agreed that hepatitis B virus (HBV) replication is reduced by hepatitis delta virus infection (HDV) and augmented by human immunodeficiency virus (HIV) infection. However, the precise nature of the interactions between HBV, HDV and HIV is controversial. The aim of this study was to evaluate the impact of HIV infection on HBV and HDV replication, and on histological scores during delta virus superinfection in HDV-positive, chronic carriers of hepatitis B surface antigen (HBsAg). We studied 38 men and six women, 15 of whom were HIV-positive and all of whom had at least one marker of HDV infection. Serum hepatitis B e antigen (HBeAg), HBV DNA, HDV RNA, anti-delta antigen antibodies (anti-HD) IgM, anti-HD IgG and hepatitis delta antigen (HDAg) were tested for in the serum and liver, respectively; anti-hepatitis C virus (HCV) antibodies were detected using a second-generation recombinant immunoblot assay. Histological specimens were scored blindly according to Knodell's classification for periportal and intralobular necrosis, portal inflammation and fibrosis. HBV DNA was detected more frequently in the HIV-positive patients than in those who were HIV-negative (25 vs 0%; P = 0.01), while markers of HDV replication (serum anti-HD IgM, serum HDV RNA and liver HDAg) were as frequent in the HIV-positive patients (69%, 40% and 50%, respectively) as in those who were HIV-negative (75%, 52% and 30%, respectively; P > 0.05). By contrast, 31% of the HIV-positive patients were serum HDAg-positive compared to only 6% of the HIV-negative patients (P = 0.001). HDV antigenaemia and anti-HD antibodies usually fluctuated in the HIV-positive patients during follow-up. The mean Knodell score was similar in the HIV-positive (11.5 +/- 3.2) and HIV-negative (10.7 +/- 2) subgroups, as was the mean semi-quantitative index of hepatic necrosis, inflammation and fibrosis. Our results provide evidence that in HDV-positive patients: (1) HIV infection counters the inhibitory effect of HDV superinfection on HBV replication; (2) serum anti-HD IgM. HDV RNA and liver HDAg are not more frequent in HIV-positive than in HIV-negative patients, suggesting that HIV infection has no effect on HDV replication (although the significance of the increased frequency of HD antigenaemia remains unclear); (3) the histological severity of liver disease is not influenced by HIV status.

Regression of Diffuse Intralobular Liver Fibrosis Associated with Visceral Leishmaniasis

Diffuse intralobular fibrosis of the liver is rare in cases of New World visceral leishmaniasis. A patient with this disease from a newly endemic area in the northernmost area of the Brazilian Amazon region was studied. Hypertrophy and hyperplasia of the phagocytic mononuclear cell system were observed, with parasitism and Disse's space fibrosis diffusely involving the liver. This description is based on a biopsy carried out after seven days of treatment with Glucantime. Another biopsy performed almost two years later showed no fibrosis, no Kupffer cell hypertrophy and hyperplasia, and no parasitism. The mechanism of fibrosis and regression is discussed.

Movement of intrapancreatic calcium in dogs with experimental pancreatic lithiasis. With special reference to the process of pancreatic calculus formation.

This study was performed to clarify the movement of calcium in the pancreas of dogs with chronic pancreatitis, using scanning and transmission electron microscopes (SEM, TEM) equipped with X-ray elemental microanalyzers. Eleven adult mongrel dogs underwent incomplete ligation of the pancreatic duct. After the procedure, the levels of pancreatic enzymes in the serum did not change for 9 mo, but the endocrine function was reduced gradually. Of all dogs, 5 revealed pancreatic sclerosis, and 2 at 9 mo had calculi, 2-4 mm in size, in the small pancreatic duct. SEM examination revealed the intralobular fibrosis and irregularity of the pancreatic duct wall, and TEM examination revealed the intralobular fibrosis and irregularity of the pancreatic duct wall, and TEM examination demonstrated the amorphous or crystalloid substances and secreted granules in the acinar lumen or ductule. In elemental analysis spectra using SEM, a high calcium peak was seen in the pancreatic duct wall. In elemental analysis spectra using TEM, a high calcium peak was observed in the amorphous or crystalloid substances, and a high ratio of Ca/K was seen in these substances. Calcium was also detected in the secreted granules or microvilli. These results suggest that there is a process of calculus formation based on the congregation of the intraductular substances containing a large quantity of calcium.

Acute pancreatitis is not a cause of chronic pancreatitis in the absence of residual duct strictures.

It has been shown that intraductal injections of bile salts into the bile-pancreatic ducts of dogs or rats were immediately followed by acute hemorrhagic pancreatitis and, some months later, by persisting chronic pancreatitis. The study described in this article was designed to test the assumption that these chronic lesions were due to ductal strictures secondary to the toxic effect of bile salts. The bile-pancreatic ducts of 100 rats were injected with 0.2 ml of a solution containing 4 microM Na taurodeoxycholate and 0.2 microM trypsin. The 66 survivors were killed at intervals from 1 day to 2 months following the induction of acute pancreatitis. Four to six sections were done in the first series, and serial 15-micron sections of the entire pancreas were taken from rats surviving 2 months. These showed that from the sixth day on, the largest ducts draining pathological areas were obstructed by fibrosis. Distal to this obstruction, intralobular ducts were dilated and their epithelia flattened or atrophied. Acini were atrophied and replaced by peri- and intralobular fibrosis. Lesions were limited to areas drained by obstructed ducts, with the rest of the parenchyma being normal. We conclude that in experimental animals, as in human beings, chronic lesions that persist after acute pancreatitis are due to duct obstruction, not to acinar necrosis.

Ursodiol in the long-term treatment of chronic hepatitis: a double-blind multicenter clinical trial

Ursodeoxycholic acid (UDCA or ursodiol) administration has been associated with a reduction of serum liver enzymes in patients with chronic liver disease and with improvement of liver histology in patients with primary biliary cirrhosis. To establish the potential therapeutic efficacy of ursodiol in chronic hepatitis, serum biochemistry and liver histology were investigated in a multicenter, double-blind placebo controlled clinical trial. Sixty patients with non-cholestatic chronic active (mild or severe) hepatitis, mainly of viral (virus C) etiology and almost completely asymptomatic, were enrolled in 3 centers: 29 were assigned to receive placebo and 31 UDCA (600 mg/day) for 1 year. Demographic, biochemical, virological and histological features were balanced between the 2 groups at the entrance into the study. Fifty-six patients (34 males, 22 females; 19 with cirrhosis; 5 HBsAg-positive; 45 anti-HCV positive) were included in the final analysis. Compliance was checked by measuring UDCA levels at the 3 follow-up visits (3, 6 and 12 months). Liver biopsy was performed at the beginning and at the end of treatment and was evaluated blindly by our pathologist (F.C.). Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gammaglutamyltransferase (GGT) levels were significantly reduced by 25% from baseline values during treatment with ursodiol but not with placebo. The efficacy of UDCA in lowering serum AST and ALT was more pronounced in the presence of cirrhosis. The semiquantitative liver histological score used remained substantially unchanged after treatment and no differences between placebo and UDCA were found for portal or periportal necrosis or inflammation, intralobular degeneration, cholestasis or fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Unusual diffuse liver fibrosis accompanying transient myeloproliferative disorder in Down's syndrome: a report of four autopsy cases and proposal of a hypothesis

Transient myeloproliferative disorder (TMD), an acute leukemia-like disorder in neonates with Down's syndrome, is characterized by spontaneous regression of abnormal blast growth. Because proliferating blasts frequently express phenotypes of megakaryocytic lineage and, as a result, this disorder resembles acute megakaryoblastic leukemia (AMKL), it would be of interest to determine whether myelofibrosis, a common complication of AMKL, is also present in TMD. Pathologic observations of four autopsy cases of TMD showed that myelofibrosis was not present in any of them, whereas intralobular diffuse liver fibrosis was present in all of them. Laboratory data of four additional cases showed hepatic dysfunction in all of them, suggesting a close association between hepatic lesions and TMD. From these results, we propose a hypothesis that the abnormal blasts with megakaryocytic properties in TMD originate from the fetal liver and cause liver fibrosis, as AMKL cells are thought to cause myelofibrosis by producing collagen-stimulating cytokines in the bone marrow. This hypothesis also seems to explain some other unique aspects of TMD.

Unusual Diffuse Liver Fibrosis Accompanying Transient Myeloproliferative Disorder in Down’s Syndrome: A Report of Four Autopsy Cases and Proposal of a Hypothesis

Abstract Transient myeloproliferative disorder (TMD), an acute leukemia-like disorder in neonates with Down's syndrome, is characterized by spontaneous regression of abnormal blast growth. Because proliferating blasts frequently express phenotypes of megakaryocytic lineage and, as a result, this disorder resembles acute megakaryoblastic leukemia (AMKL), it would be of interest to determine whether myelofibrosis, a common complication of AMKL, is also present in TMD. Pathologic observations of four autopsy cases of TMD showed that myelofibrosis was not present in any of them, whereas intralobular diffuse liver fibrosis was present in all of them. Laboratory data of four additional cases showed hepatic dysfunction in all of them, suggesting a close association between hepatic lesions and TMD. From these results, we propose a hypothesis that the abnormal blasts with megakaryocytic properties in TMD originate from the fetal liver and cause liver fibrosis, as AMKL cells are thought to cause myelofibrosis by producing collagen-stimulating cytokines in the bone marrow. This hypothesis also seems to explain some other unique aspects of TMD.

Proliferation of collagen fibrils and Ito cells in the liver after Japanese sake administration in undernourished rats as demonstrated by scanning electron microscopy.

Intralobular fibrosis of the liver was induced in undernourished rats by administering Japanese sake for 12 days. Control rats administered the equivalent calories with glucose solutions did not show any fibrosis. In the sake group, Ito cells were increased and often clustered under the scanning electron microscope (SEM). Many collagen fibrils 0.1 microns in diameter twisted around Ito cells which had numerous microvillous projections. On the contrary, fibrils were not increased and Ito cells had rather smooth surfaces in the control group. The number of Ito cells counted under the SEM at 500 magnifications was increased in the sake group (mean +/- standard deviation; 70 +/- 23/mm2) as compared to the control group (44 +/- 9; P less than 0.01). The fact that Ito cells had proliferated and were tangled with collagen fibrils in the sake group was demonstrated three-dimensionally by SEM.