Hiperbilirrubinemia: visión del patólogo / Hyperbilirubinemia: pathologist's view

Los niveles de bilirrubina sérica normal en el adulto varían entre 0,3 mg/dL y 1,2 mg/dL, y su valor está determinado por la tasa de captación hepática, conjugación y excreción. La ictericia se hace evidente cuando los niveles de bilirrubina sérica se elevan por encima de 2,5 mg/dL a 3 mg/dL, siendo un indicador de enfermedad subyacente. La bilis es producida por los hepatocitos y fluye desde los canalículos, canales de Hering, conductos biliares intrahepáticos, conductos hepáticos derechos e izquierdos hasta llegar al duodeno. A nivel histopatológico, cualquier entidad que lleve a la acumulación intrahepática de bilis por disfunción hepatocelular u obstrucción biliar genera colestasis, que se observa en la biopsia hepática como la acumulación de tapones de color marrón verdoso de pigmento biliar en los hepatocitos, y secundariamente se observan los canalículos dilatados. Las causas de colestasis intrahepática son diversas e incluyen enfermedades como colangitis biliar primaria, colangitis esclerosante primaria, hepatitis autoinmune, hepatitis virales y toxicidad medicamentosa. Esta revisión tiene como objetivo analizar algunos tipos de hiperbilirrubinemia, resaltando sus características histopatológicas.

Normal serum bilirubin levels in adults range from 0.3 mg/dL to 1.2 mg/dL, and its value is determined by the rate of hepatic uptake, conjugation, and excretion. Jaundice becomes apparent when serum bilirubin levels rise above 2.5 mg/dL to 3.5 mg/dL and is an indicator of underlying disease. Bile is produced by hepatocytes and flows from the canaliculi, Hering's canals, intrahepatic bile ducts, and right and left hepatic ducts to the duodenum. Pathologically, any condition that leadsto intrahepatic accumulation of bile due to hepatocellular dysfunction or biliary obstruction, generates cholestasis, which is observed in liver biopsy as the accumulation of greenish-brown deposits of bile pigment in hepatocytes, with dilated canaliculi. The causes of intrahepatic cholestasis are diverse and include diseases such as primary biliary cholangitis and primary sclerosing cholangitis, autoimmune hepatitis, viral hepatitis, and drug toxicity. This review aims to analyze some types of hyperbilirubinemia, highlighting their histopathological characteristics.

Histologic and Molecular Pathogenesis of Gallbladder Cancer / 대한췌담도학회지

Adenocarcinoma is the major histology of gallbladder cancer. There are three subtypes of adenocarcinoma of the gallbladder: biliary, intestinal, and gastric foveolar subtypes. Also, there are three premalignant lesions of gallbladder adenocarcinoma: adenoma, biliary intraepithelial neoplasia (BilIN), and intracystic papillary neoplasm (ICPN). Premalignant lesion is hyperplasia of dysplastic epithelial cells with no evidence of stromal invasion. BilIN is invisible in gross inspection but can be microscopically identified around invasive tumor or chronic cholecystitis. ICPN is grossly identified as exophytic polypoid mass or diffuse friable thickening of mucosa and composed of mucinous epithelial cells with papillary and tubular arrangement. Dysplasia of BilIN and ICPN is classified by using a three-tiered system and high grade dysplasia is the same group with carcinoma in situ. Adenoma and ICPN have some ambiguities in definition and re-establishment of diagnostic criteria is needed for reproducibility of diagnosis. KRAS, TP53, and CDKN2A are the representative altered molecules in gallbladder cancer. Molecular alteration during dysplasia-carcinoma sequence is too heterogenous depending to the risk factors and type of premalignant lesion to explain the whole process by single process. Over-expression of COX2, mutation of TP53, impairment of mitochondrial DNA were reported in early hyperplastic or metaplastic epithelium. Loss of heterozygosity (LOH) of 3p, 8p chromosomes and amplification of HER2 were reported in low grade dysplasia and LOH of 9p, 18q, 22q, 17p chromosomes and mutation of CDK2A were reported in high grade dysplasia/carcinoma in situ.

Effects of Jinhuang Yidan Granule on the bile compositions of primary bile duct pigment calculus patients / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effects of Jinhuang Yidan Granule (JYD) on the bile compositions of primary bile duct pigment calculus patients.</p><p><b>METHODS</b>Sixty-six patients with primary bile duct pigment calculus were randomly assigned to the control group (who took no Chinese medicine) and the JYD group (who took JYD). The bile from T-tube during the operation, 3, 10, and 40 days after medication were examined. The contents of bile acids, bilirubin (conjugated bilirubin, mono-conjugated bilirubin), glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anion, and other components were detected and compared.</p><p><b>RESULTS</b>Three days after taking JYD, the total bile acids increased, the total bilirubin and beta-glucuronidase decreased, showing statistical significance when compared with the control group (P < 0.05). In the JYD group, the total bile acid increased, the total bilirubin, the conjugated bilirubin, the mono-conjugated bilirubin, glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anions decreased 10 and 40 days after medication, showing statistical significance when compared with the control group (P < 0.05, P < 0.01). The level of the total bile acid increased, the levels of the total bilirubin, the conjugated bilirubin, the mono-conjugated bilirubin, glucoprotein, calcium ion, beta-glucuronidase, superoxide radical anions decreased after 40-day medication in the two groups, showing statistical significance when compared with the peri-operative indices of the same group (P < 0 05, P < 0.01).</p><p><b>CONCLUSIONS</b>JYD could significantly improve the pathologic bile compositions of the bile duct calculus, improve the environment of the biliary tract, showing certain preventive and therapeutic effects on bile pigment calculus of the primary bile duct calculus. Better effects may be obtained by long-term taking.</p>

A comparative study of serum lipid profile and gallstone disease.

The diseased gallbladder is one of the commonest specimens submitted to the surgical pathology laboratory in North India. Obesity is associated with a linear increase in gallstone formation. It has been observed that the plasma lipoprotein profile of patients with gallstones differs markedly from that of healthy subjects. Serum lipid profile was done by enzyme kit method. All the gallstones received were categorized morphologically and examined biochemically. The age range of 200 cases was 13 to 77 years with a mean of43.75 +/- 13.39 years. There were 171 females (85.5%) and 29 males (14.5%) with male to female ratio of 1: 5.8. The stones containing both cholesterol and bile pigments were the most common (129 cases, 84.87%); while pure cholesterol stones were seen in 23 cases (11.50%) and pigment stones were infrequent (1 case, 0.65%). On lipidogram of patients in the study group, mean serum total cholesterol was 155.50 +/- 43.03 mg/dL, mean serum triglycerides was 100.49 +/- 45.23 mg/dL, mean HDL cholesterol was 46.71 +/- 15.20 mg/dL, mean LDL cholesterol was 87.94 +/- 36.85 mg/dL and mean VLDL cholesterol was 20.84 +/- 11.97 mg/dL. Serum total cholesterol values were significantly higher in patients older than 39 years as compared to patients < or =39 years (161.44 +/- 42.32 mg/dL vs. 145.79 +/- 32.96 mg/dL, p < 0.05). But the observed mean values in both of these subgroups were within the normal range i.e. <200 mg/dL. No significant difference was observed in the mean serum triglyceride values between male and female patients. The findings of this study did not indicate any role of serum lipid profile in the formation of gallstones. However the higher mean values of serum total cholesterol and serum triglycerides in patients older than 39 years of age may be explained by increasing age.

Effect of clearing heat and removing dampness method on formation of pigment gallstones in rabbits / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe dynamically the effect of drugs for clearing heat and removing dampness (CHRD) on biliary components in rabbits with pigment gallstones (PGS).</p><p><b>METHODS</b>Forty rabbits were established into PGS model and randomly divided into 3 groups, the bacterial infection group, the CHRD low-dose group and the CHRD high-dose group. Besides, a normal group was set up with healthy rabbits for control. Changes of total bilirubin (TB), unconjugated bilirubin (UCB), total bile acid (TBA), Ca2+, bacterial and endogenous beta-glucuronidase (beta-Gase) in bile were observed.</p><p><b>RESULTS</b>CHRD drugs significantly decreased the contents of UCB, Ca2+, bacterial and endogenous beta-Gase (P < 0.05), and increased TBA in bile (P < 0.05).</p><p><b>CONCLUSION</b>CHRD drugs have good effect in reducing the lithogenesis of the pigment gallstones.</p>

The relationship between Oddi's sphincter and bile duct pigment gallstone / 中华外科杂志

<p><b>OBJECTIVE</b>To investigate the relationship between anatomic abnormalities and malfunction of Oddi sphincter with formation of bile duct pigment gallstone.</p><p><b>METHODS</b>One hundred and twenty-three patients with a T tube after cholecystectomy and choledochotomy were divided into reflux group and control group by measuring the amounts of radioactivity of (99m)Tc-DTPA in the bile. Among them 53 were selected randomly to undergo choledochoscopic manometry. Basal pressure of Oddi's sphincter (SOBP), amplitude of Oddi's sphincter (SOCA), frequency of contraction (SOF), duration of contraction (SOD), duodenal pressure (DP), common bile duct pressure (CBDP) were scored and analyzed. The level of plasma motilin and serum gastrin of 45 patients and 12 healthy volunteers were measured by radioimmunoassay. The incidence rates of duodenal descending part diverticulum in patients with bile duct pigment stones, patients without alimentary tract diseases, patients with gallbladder polyps, patients with gallbladder stones were studied by means of barium meal examination. The incidence rates of intraduodenal peri-ampullary diverticulum in patients with primary bile duct pigment stones, patients with bile duct stone and gallbladder stones, patients with bile duct stones originating from the gallbladder, patients with inflammation and stricture of the extremity of bile duct and papilla, patients with cancer of the extremity of bile duct and papilla, patients with post-cholecystectomy syndrome were detected by duodenoscope.</p><p><b>RESULTS</b>Of the patients, 44 were detected with duodenal-biliary reflux (35.8%). SOBP, SOCA and CBDP in the reflux group were much lower than those in control group (P < 0.001). The level of serum gastrin and plasma motilin of the reflux group were much lower than those of control group (P < 0.01). Positive correlation was found between level of motilin and SOBP while level of gastrin was positively correlated with SOBP and CBDP. The incidence of duodenal diverticulum in patients with bile duct pigment stone was 36.62%, which was higher than that of the other 3 groups. The incidence rate of intraduodenal peri-ampullary diverticulum in patients with primary bile duct pigment stone was higher than that of patients with inflammation and stricture of the extremity of bile duct and papilla, patients with cancer of the extremity of bile duct and papilla and patients with bile duct stones originating from the gallbladder.</p><p><b>CONCLUSIONS</b>The patients with bile duct pigment stone have apparent duodenal-biliary reflux and infection of the bile duct. The state of structure and function of Oddi's sphincter is correlated significantly with bile duct pigment stone. The anatomic abnormalities and malfunction of Oddi's sphincter played an important role in the formation of bile duct pigment stone.</p>

A Case of Metastatic Hepatocellular Carcinoma of the Ovary: An Immunohistochemical Study and Literature Review

Hepatocellular carcinomas rarely metastasize to the ovaries. To our knowledge, only nine cases of metastatic hepatocellular carcinoma of the ovary have been reported in the literature. Here, we present an additional case in which an ovarian lesion was the initial presentation in a 43-year-old female patient. An exploratory laparotomy revealed a left ovarian solid mass measuring 6.5*4.0*3.5 cm, with a lobulated greenish brown sectioned surface. A subsequent ultrasonogram and CT scan revealed a concurrent hepatic mass, and laboratory tests showed high serum AFP and CA125 levels. Microscopically the tumor showed predominantly solid and trabecular patterns, and intercellular canaliculi containing bile pigments. A postoperative hepatic biopsy confirmed the hepatocellular carcinoma. The main differential diagnosis involved ovarian metastasis of the hepatocellular carcinoma, the hepatoid carcinoma of the ovary with liver metastasis, and a hepatoid yolk sac tumor. Diagnosis in such cases should be reached by careful clinical evaluation and a thorough pathologic examination accompanied by a histochemical and immunohistochemical work-up.

Genetic and Clinical Characteristics of Multiplex Schizophrenia Families / 신경정신의학

OBJECTIVES: This study aims at exploring genetic and clinical characteristics of multiplex Korean families with schizophrenia. METHODS: Thirty-three families having two or more schizophrenics by DSM-IV criteria within the second degree relatives were obtained from the clinics of general hospitals and mental hospitals. Sixty-nine affected and forty-five unaffected subjects from these families were interviewed using Korean version of Diagnostic Interview for Genetic Studies. Krawieka Rating Scale and The Schedule for the Deficit Syndrome were also applied for further evaluation of psychopathologies of the patients. Patterns of inheritances of the disease were analyzed by the inspection of the pedigrees. Parent-of-origin effect was evaluated by the comparison of the occurrence rate and the clinical characteristics between the subgroups of maternal and paternal origins. RESULTS: There were similar rates of maternal and paternal transmission in the families for which unilineal transmission of the disease was estimated. Only one family showed bilineal transmission. Observed patterns of transmission were not compatible with the recessive single locus model or sex-linked model. The most frequently observed non-schizophrenic disorders in these families were personality disorders/traits of schizophrenia spectrum. We could not find any clinical characteristics which might be unique to the patients from multiplex families. Parent-of-origin effect was not suggested. CONCLUSION: This study provides preliminary clinical and genetic data on the multiplex schizophrenia families which could be used for the determination of the genetic parameters and the boundaries of the phenotype in the linkage analyses.

Expression of MUC3, MUC5AC, MUC6 and Epidermal Growth Factor Receptor in Gallbladder Epithelium according to Gallstone Composition / 대한소화기학회지

BACKGROUND/AIMS: Gallbladder (GB) mucin is one of the key factors in the gallstone formation. However, there is little information about the diversity of mucin secretion according to the stone composition. Epidermal growth factor receptor (EGFR) functions in proliferation including mucin secreting goblet cell hyperplasia. We compared the expressions of MUC3, MUC5AC, MUC6 and EGFR in the GB epithelium with cholesterol gallstones (GB-chol) group and pigment gallstones (GB-pig group). METHODS: GBs from elective laparoscopic cholecystectomy for the gallstone disease were studied. Stone composition was analyzed by the spectrophotometer. Immunohistochemical stain was performed using each monoclonal antibody. The percentage of stained proportion was scored by the NIH image program and the results were compared between both groups. RESULTS: Total 20 patients were enrolled (10 patients with cholesterol gallstones, 10 patients with pigment gallstones). The percentages of stained proportion for MUC3, MUC5AC, and MUC6 were 42+/-27%, 31+/-15%, and 17+/-9%, respectively in GB-chol group and 32+/-22%, 33+/-23%, and 15+/-10%, respectively in GB-pig group (p>0.05). The expression of EGFR was 50% (5/10) in the GB-chol group and 80% (8/10) in the GB-pig group respectively. CONCLUSIONS: There was no difference in the expressions of MUC3, MUC5AC, and MUC6 between the two groups. Further studies are needed to elucidate the role of EGFR in the gallstore formation.

Surgical practice in symptomatic and asymptomatic gallstone disease.

AIMS: To determine the surgical practice in individuals with symptomatic and asymptomatic gallstone disease using a questionnaire survey. METHODS: A questionnaire was sent to 724 patients with gallstone disease. Details of symptoms, duration of illness, nature of treatment including surgery, color of gallstones retrieved and postoperative follow-up particulars were obtained. RESULTS: The study group included 225 (54%) men; there was a rising trend of prevalence of gallstones in men with increasing age (p<0.05). A third of the patients (142 [34%]) were symptomatic. The mean duration of symptoms was 12.1 months. One hundred and ninety seven patients (48%), including 90 asymptomatic ones, underwent cholecystectomy. Most patients (92.5% of those symptomatic and 76.6% of those asymptomatic) underwent cholecystectomy within one year of diagnosis. Eight asymptomatic patients underwent surgery 3 years or more after diagnosis. The predominant color of stones retrieved was black or brown (57%) or mixed (39%). CONCLUSIONS: A majority of patients with gallstone disease had cholecystectomy within one year of diagnosis. Black or brown pigment stones were the dominant types of gallstones.

Fibrolamellar Hepatocellular Carcinoma with Cytokeratin 7 Expression: A Case Report

Fibrolamellar carcinoma (FLC) is a rare variant of hepatocellular carcinoma (HCC). A 26-year-old female presented a hepatic mass and mild elevation of liver enzymes. Viral markers were negative, and levels of tumor markers were normal. Radiologically, the mass was well demarcated with central dot-like calcification and hypervascularity. Under the diagnosis of hepatocellular carcinoma, right lobectomy was performed. The tumor was grayish yellow with central fibrosis and focal hemorrhage and invaded a septal bile duct. Non-neoplastic liver was unremarkable. Microscopically, the tumor consisted of large polygonal cells in sheets, cords, and pseudoglands that were interwound by dense collagenous stroma. Tumor cells had abundant deeply eosinophilic cytoplasm and large nuclei with prominent nucleoli. Intracellular bile pigments and pale bodies were present. Tumor cells were diffusely immunostained for cytokeratin 7 (CK7), but not for cytokeratin 20 (CK20). Strong expression of CK7 in the present case suggests dual differentiation of FLC.

A Case of Methimazole-Induced Cholestatic Jaundice with Steroid Therapy / 대한내분비학회지

Cholestatic jaundice caused by imidazole derivatives is a rare complication of antithyroid drug therapy. We present a case of cholestatic jaundice with systemic hypersensitivity reaction, which developed in a 27-year old male one day after exposure to methimazole. The patient showed clinical improvement and gradual resolution of jaundice after the discontinuation of methimazole and treatment with prednisolone. Histologic findings of liver revealed bile pigment, predominantly in centrilobular area, and infiltration of chronic inflammatory cells in a few portal area without evidence of degeneration or necrosis of hepatocytes. Methimazole could be presumed as etiologic agent from clear chronological relationship and the lack of other causative factors. We report this unusual case with review of literature.

Current development in the pathogenesis of gallstones.

Demonstration in 1968, of the association of cholesterol supersaturation of bile with cholesterol gallstones paved the way to a physical-chemical basis for gallstone formation. It however, soon became clear that other factors including nucleation of cholesterol crystal, binding together of these crystals with mucin, and hypomotility of the gallbladder played an equally important role in gallstone formation. Although the molecular events that underlie these processes are far from clear, many loose ends are beginning to tie. One knot recently tied is that an increase in biliary arachidonyl lecithin may lead to increased prostanoid synthesis which may be responsible for increased mucin secretion as well as gallbladder hypomotility. Research on similar lines is being done to unravel the pathogenesis of pigment gallstones, but much less has been gained in that field. An interesting outcome of some recent work is that biliary micelles and vesicles are important not only for the solubilisation of cholesterol but also for that of bilirubin and calcium which are the major constituents of pigment gallstones. This observation opens a common ground for the formation of both types of gallstones.

Cholelithiasis--areview of 130 cases.

One hundred and thirty cases of cholelithiasis were studied in the surgical wards of the Institute of Postgraduate Medicine and Research, Dacca. Geographical distribution, pattern of clinical features, results of biochemical, microbiolgical, histopathological and other investigations have been recorded.