Cases Of Chronic Viral Hepatitis Research Articles

IL‐8 expression by biliary epithelial cells is associated with neutrophilic infiltration and reactive bile ductules

Reactive bile ductule is a non-specific feature of various hepatobiliary diseases, and is not infrequently accompanied by neutrophilic infiltration. Recently, biliary epithelial cells have been shown to secrete cytokines and chemokines and to express components of the mucosal immune system such as Toll-like receptors. We examined the expression of a neutrophil chemo-attractant, interluekin (IL)-8, in bile ductular cells to clarify the histogenesis of reactive bile ductules with neutrophilic infiltration using human liver tissues (eight cases of chronic viral hepatitis, seven cases of liver cirrhosis (LC), seven cases of sepsis, 11 cases of extrahepatic biliary obstruction (EBO), three cases of fulminant hepatitis (FH), five cases of primary biliary cirrhosis, and three cases of primary sclerosing cholangitis). Human neutrophil peptides 1-3 (HNP1-3) were used as markers of neutrophils. Immunohistochemically, IL-8 was detected in bile ductules in various diseased livers. HNP1-3-positive neutrophils were significantly dense around IL-8-positive bile ductules compared with IL-8-negative ductules in septic liver, LC, EBO, and FH. Experiments in vitro showed that cultured human biliary epithelial cells expressed and secreted IL-8 in response to lipopolysaccharide and also IL-1beta and tumour necrosis factor-alpha. Neutrophilic infiltration around reactive bile ductules may be related to the IL-8 expressed in bile ductular epithelia, possibly induced by bacterial components and proinflammatory cytokines released locally.

Characterization of biliary intra‐epithelial lymphocytes at different anatomical levels of intrahepatic bile ducts under normal and pathological conditions: Numbers of CD4+CD28– intra‐epithelial lymphocytes are increased in primary biliary cirrhosis

Distribution of intra-epithelial lymphocytes along intrahepatic biliary tree (bIEL), and their density and phenotype were examined in normal and diseased livers, particularly in primary biliary cirrhosis (PBC). Immunohistochemically, bIEL were examined in 28 normal livers, 13 cases of chronic viral hepatitis (CVH), 13 cases of PBC, five cases of primary sclerosing cholangitis (PSC), seven cases of extrahepatic biliary obstruction (EBO), and 16 hepatolithiatic livers. In normal livers, bIEL were relatively dense at large and septal bile ducts compared to interlobular ducts. Most of them were positive for CD3 and CD8, while a few were positive for CD4, CD20 and CD57. In CVH, PSC and EBO, neither distribution, phenotype nor density of bIEL differed from normal liver. In hepatolithiasis, numbers of CD8(+)bIEL were increased in stone-containing ducts. In PBC, numbers of CD4(+)CD28(-)bIEL, which are reportedly responsible for target tissue destruction in autoimmune diseases, were markedly increased in damaged interlobular ducts. In conclusion, CD3(+)CD8(+)bIEL may be involved in immune homeostasis of intrahepatic bile ducts in normal livers and in CVH, PSC and EBO. Altered distribution and phenotypes of bIEL in PBC and hepatolithiasis may reflect their participation in biliary lesions. Increased CD4(+)CD28(-)bIEL in damaged bile ducts of PBC may be related to immune-mediated biliary damage.

Serum Iron Levels and Hepatic Iron Overload in Nonalcoholic Steatohepatitis and Chronic Viral Hepatitis

Our objective was to determine the effect of serum iron levels and hepatic iron overload on hepatocellular damage in nonalcoholic steatohepatitis (NASH) and to compare this with chronic viral hepatitis. Twenty-five patients who had elevated transaminase levels on at least two occasions, without any evidence of viral and autoimmune hepatitis and diabetes, without a history of significant alcohol use, and with a liver biopsy consistent with NASH were enrolled in the study. Twenty-five patients with chronic viral hepatitis (13 patients with chronic hepatitis C and 12 with chronic hepatitis B) who were not under any antiviral treatment were taken as controls. Metabolic factors were studied in the NASH and chronic hepatitis groups. Biopsy specimens were stained with hematoxylin-eosin, and the grade of steatosis and the stage of fibrosis were evaluated as I, II, or III, I being mild and III being severe. Iron overload in the hepatic tissue was studied by Prussian blue staining. Serum ALT, AST, ALP, GGT, globulin, and ferritin levels were comparable in both steatohepatitis and chronic viral hepatitis groups. However, patients with chronic hepatitis had a lower albumin level and a higher serum iron level, with higher transferrin saturation. Among patients with NASH, mild, moderate, and severe steatosis was found in 7, 10, and 8 patients, respectively. Inflammatory infiltration was grade I in 24 patients and grade III in 1 patient. Fibrosis was mild in 12 patients and 13 patients had no fibrosis. Among patients with chronic viral hepatitis, inflammatory infiltration of grade I was seen in 11 patients, grade II in 11 patients, and grade III in 3 patients. Fibrosis was mild in 9 patients, moderate in 13 patients, and severe in 2 patients; 1 patient had no fibrosis. Compared to patients with NASH, those with chronic viral hepatitis cases had more severe inflammatory infiltration and fibrosis (P < 0.01). While five patients with chronic viral hepatitis had mild iron overload, patients with NASH had no hepatic paranchymal iron overload. Neither NASH nor chronic viral hepatitis revealed a relationship between hepatic iron overload and disease activity. This suggests that the iron overload actually may be a result of hemachromatosis gene mutation. The absence of hepatic parenchymal iron overload in the NASH group and only mild iron accumulation in the chronic hepatitis group may be explained by a lower frequency of the gene mutation in our country.

Apoptosis in chronic viral hepatitis parallels histological activity: An immunohistochemical investigation using anti‐activated caspase‐3 and M30 Cytodeath antibody

Apoptosis is implicated as a major pathogenic mechanism in chronic hepatitis B and C. Previous studies of the relationship between apoptotic rates and histological necroinflammatory activity have produced conflicting results. Hepatocyte apoptosis was assessed in liver tissue from 32 cases of chronic viral hepatitis, seven cases of hepatocellular carcinoma (HCC) and six cases of steatohepatitis as non-viral disease controls and eight cases of control liver. Apoptotic rates were measured using H&E morphological assessment and immunohistochemical staining with antibodies to activated caspase-3 and M30. Histological necroinflammatory activity of viral hepatitis cases was scored using the Knodell scoring system, and the cases were divided according to their score into group 1 (mean 2.43 +/- 0.48) and group 2 (mean 7.80 +/- 0.49). Apoptotic indices were significantly higher in group 2 than group 1 using H&E (11.53 +/- 2.70 vs. 0 +/- 0, P=0.015) and activated caspase-3 (22.01 +/- 5.27 vs. 1.79 +/- 1.79, P=0.03) methods but were not significantly higher with M30 (3.80 +/- 1.74 vs. 0 +/- 0, P=0.207). Apoptotic scores using an antibody to activated caspase-3 are significantly higher in cases of chronic viral hepatitis with greater histological necroinflammatory scores, supporting a central role for apoptosis in disease pathogenesis. This method offers an alternative to routine histological assessment for measuring disease activity.

Determination of platelet-activating factor by reverse phase high-performance liquid chromatography and its application in viral hepatitis

To detect the platelet-activating factor (PAF) and the plasma or serum levels of tumor necrosis factor-alpha (TNF-alpha) malondialdehyde (MDA), endotoxin (ET) and to discuss their significance in various types of viral hepatitis. PAF, TNF-alpha, MDA, and ET levels in 60 controls, 16 cases of acute viral hepatitis, 71 cases of chronic viral hepatitis, 19 cases of severe viral hepatitis were detected by reverse phase high-performance liquid chromatography (rHPLC), bio-assay, ELISA, thiobarbituric acid (TBA), and limulus lysate test (LLT), respectively. The rHPLC was more sensitive and specific than bio-assay (r = 0.912, P<0.01). The plasma levels of PAF, TNF-alpha, MDA, and ET in patients with viral hepatitis were higher than those in controls (P<0.01). rHPLC is more reliable and accurate for the detection of PAF.

Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts†

Fractalkine is a chemokine with both chemoattractant and cell-adhesive functions, and in the intestine it is involved with its receptor CX3CR1 in the chemoattraction and recruitment of intraepithelial lymphocytes. We examined the pathophysiological roles of fractalkine and CX3CR1 in normal and diseased bile ducts. Expression of fractalkine and CX3CR1 were examined in liver tissues from patients with primary biliary cirrhosis (17 cases) and controls (9 cases of primary sclerosing cholangitis, 10 cases of extrahepatic biliary obstruction, 20 cases of chronic viral hepatitis C, and 18 cases of histologically normal livers). Expression of fractalkine in biliary epithelial cells (BECs) in response to cytokine treatments was examined using a human cholangiocarcinoma cell line (HuCC-T1) and human intrahepatic BEC line. The chemotaxis of CX3CR1-expressing monocytes (THP-1) toward fractalkine was assayed using chemotaxis chambers. Fractalkine messenger RNA/protein were expressed on BECs of normal and diseased bile ducts, and their expression was upregulated in injured bile ducts of primary biliary cirrhosis. CX3CR1 was expressed on infiltrating mononuclear cells in portal tracts and on CD3(+), CD4(+), and CD8(+) intraepithelial lymphocytes of injured bile ducts in primary biliary cirrhosis. Fractalkine messenger RNA expression was upregulated in two cultured BECs on treatment with lipopolysaccharide and Th1-cytokines (interleukin 1beta, interferon gamma, and tumor necrosis factor alpha). THP-1 cells showed chemotaxis toward fractalkine secreted by cultured cells. In conclusion, Th1-cytokine predominance and lipopolysaccharide in the microenvironment of injured bile ducts resulting from primary biliary cirrhosis induce the upregulation of fractalkine expression in BECs, followed by the chemoattraction of CX3CR1-expressing mononuclear cells, including CD4(+) and CD8(+) T cells, and their adhesion to BECs and the accumulation of biliary intraepithelial lymphocytes.

Hepatitis C virus infection during pregnancy in North India

Hepatitis C virus (HCV) is responsible for 20% of cases of acute viral hepatitis and nearly 50% of cases of chronic viral hepatitis. Most persons acutely infected with HCV will develop a persistent infection and nearly 70% will experience chronic necroinflammation of the liver. Information concerning potential risk factors for HCV infection is provided by studies conducted on blood donors on patients with chronic liver disease and on individuals with a history of intravenous drug use. The present study aims to assess the seroprevalence of anti-HCV antibodies in healthy asymptomatic pregnant women from the Indian subcontinent. (excerpt)

Oxidized low density lipoprotein in liver tissue samples of our nash patients, alcoholic and chronic viral hepatitis cases

Oxidized low density lipoprotein in liver tissue samples of our nash patients, alcoholic and chronic viral hepatitis cases

Management of chronic hepatitis C and prevention of hepatocellular carcinoma.

Hepatitis C virus (HCV) infection is responsible for more than a half of the cases of chronic viral hepatitis in Japan. About 20% of patients who are chronically infected with the virus develop cirrhosis about 20-30 years after the infection, with hepatocellular carcinoma developing in about 5% of patients a year. The only drug that effectively reduces the virus is interferon, but complete eradication of the virus can be obtained in only 30%-40% of treated patients. Reevaluation of the predictive factors to eradicate the virus by 24-week interferon therapy showed that the genotype other than 1b, a low virus load, and multiple amino acid substitutions in the interferon sensitivity determining region (ISDR) of genotype 1b are statistically significant predictive factors. Amino acid substitution in the PePHD domain of the E2 protein was rare and was unrelated with the outcome of interferon therapy. The fluctuation of the virus titer measured by branched DNA during a 2-year observation period was less that 10-fold in most patients, and amino acid substitutions in the ISDR were rare in such patients, suggesting that one point measurement of these parameters may be useful to select candidates for interferon therapy. A comparison of patients treated with interferon and untreated patients from the viewpoint of cancer prevention showed only a slight decrease in the risk of treated patients developing hepatocellular carcinoma. However, patients who showed normal alanine amino-transaminase (ALT) irrespective of virus clearance showed a significantly reduced risk of liver carcinogenesis. Similarly, a retrospective study to evaluate the long-term preventive effect of glycyrrhizin on hepatocellular carcinoma development showed that the therapy was effective in lowering the ALT value and in preventing liver carcinogenesis.

In situ detection of telomerase enzymatic activity in human hepatocellular carcinogenesis.

Telomerase enzymatic activity has been detected in most human malignant tumours including hepatocellular carcinoma. In order to assess the cellular source, the topographic distribution, and the chronology of telomerase re-expression during human liver carcinogenesis, an in situ technique derived from the standard TRAP (telomeric repeat amplification protocol) assay was set up that allowed the detection of telomerase enzyme activity at the cellular level on frozen liver tissue sections. In situ TRAP (ISTRAP) was performed on 27 hepatocellular carcinomas (HCCs) and 57 non-tumour livers, including normal liver without HCC, liver samples adjacent to tumour with and without hepatic cirrhosis, and biopsies of chronic hepatitis. In HCC, telomerase was detected in the nuclei of liver tumour cells in 23/27 cases (85%), with a heterogeneous distribution within the tumour. This signal was also detected in clusters of hepatocytes in 16/26 (61%) samples of liver adjacent to HCC, in 10/23 (43%) cases of chronic viral hepatitis without adjacent HCC, and in scattered nuclei of 2/8 histologically normal livers. Comparison of the results obtained with ISTRAP and standard TRAP assays on tissue extracts suggests a gain in sensitivity with the in situ technique. This study confirms that telomerase is expressed in most HCCs and suggests that focal telomerase reactivation is an early event during human liver carcinogenesis. ISTRAP is a sensitive technique that allows the study of telomerase expression in the morphological context.

PCR and in situ hybridization studies of telomerase subunits in human non-neoplastic livers.

Telomerase, a ribonucleoprotein enzyme associated with cellular immortality, consists of human telomerase RNA component (hTERC), human telomerase protein 1 (hTEP1), and human telomerase reverse transcriptase (hTERT). In this study, the expression of these subunits was examined in non-neoplastic livers [13 cases of chronic viral hepatitis (CVH), 16 of primary biliary cirrhosis (PBC), two of primary sclerosing cholangitis, and six normal livers], using the reverse transcription-polymerase chain reaction (RT-PCR), nested PCR, and in situ hybridization (ISH). Six hepatocellular carcinoma (HCC) cases and one colonic cancer were used as positive controls. Telomeric repeat amplification protocol (TRAP) assay disclosed distinct telomerase activity in all positive controls and weak telomerase activity in non-neoplastic livers in 4 of 13 CVH cases and 5 of 16 PBC cases. By RT- and nested PCR, both hTERC and hTEP1 mRNA were detectable in all non-neoplastic liver tissues; ISH revealed hTERC and hTEP1 mRNA in the periportal and periseptal hepatocytes and inflammatory mononuclear cells in those cases examined. ISH revealed hTERT mRNA only in a few infiltrating mononuclear cells in 3 of 13 CVH and 2 of 16 PBC livers and these five cases were also positive by TRAP assay. In four of these five cases, hTERT mRNA was also detectable by nested PCR, suggesting that hTERT mRNA in the non-neoplastic liver is expressed by infiltrating mononuclear cells. Biliary epithelial cells were totally negative for these human telomerase subunits. Three subunits were constantly detected in all positive controls by ISH as well as by RT- and nested PCR. The finding that hTERC and hTEP1 mRNA, but not hTERT mRNA, were detectable in the non-neoplastic hepatocytes suggests that telomerase is present but not activated and that additional factor(s) are necessary for the expression of hTERT mRNA in the hepatocytes, along with immortalization and neoplastic transformation.

Hepatitis C: natural history, diagnosis, and management.

The virology, epidemiology, clinical spectrum, diagnosis, and management of hepatitis C are reviewed. Hepatitis C infection is responsible for most cases of chronic viral hepatitis in the United States and is the major reason for liver transplantation. Hepatitis C virus (HCV) is divided into six major genotypes, with type 1 being the most prevalent in the United States. Direct percutaneous exposure is the main route of HCV transmission. Diagnosis of the infection is made by HCV antibody testing or direct detection of HCV RNA in serum. Liver biopsy is recommended for evaluating disease severity before treatment is started. The currently approved treatment for patients with chronic hepatitis C who have elevated liver transaminases and compensated liver disease consists of interferon alfa alone or in combination with ribavirin. Rates of sustained biochemical and virological responses in the range of 20-40% have been reported for a 12-month regimen of interferon alfa. Combination therapy with ribavirin improves these rates. Response rates are lower in patients with HCV genotype 1, a serum HCV RNA concentration higher than 1 million copies/mL, and cirrhosis. In patients who relapse after an initial response to interferon alfa, retreatment with interferon alfa plus ribavirin or with a higher dosage of interferon alfa is recommended. New agents under development for use against hepatitis C include viral enzyme inhibitors, ribozymes and antisense oligonucleotides, and immunomodulators. Further research is needed to optimize existing strategies for treating hepatitis C and to develop new, more effective therapies. Ultimately, combination therapies may hold the key.

Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation.

Cyclooxygenase (COX) is a key enzyme in the synthesis of prostanoids. Two isoforms of this enzyme have been identified: COX-1 and COX-2. Recent studies have suggested that COX-2, but not COX-1, may play a role in colorectal tumorigenesis. In the present study, we investigated the expression of COX-2 as well as COX-1 in human hepatocellular carcinoma (HCC) tissues using immunohistochemistry and immunoblotting. Forty-four surgically resected HCC tissues with adjacent nontumorous livers (NTs), involving 17 cases of chronic viral hepatitis and 27 cases of cirrhosis, and 7 surgically resected, histologically normal liver tissues were used. The well-differentiated HCC expressed COX-2 more frequently and strongly than less-differentiated HCC or hepatocytes of NTs. Less-differentiated HCCs expressed less COX-2 than hepatocytes of NTs, which showed scattered, strong COX-2 expression. Histologically normal liver was weakly positive for COX-2. The expression of COX-1 was weaker than that of COX-2 in hepatic neoplastic and non-neoplastic parenchymal cells. An enhanced expression of COX-1 was not observed in well-differentiated HCCs. Immunoblotting also confirmed up-regulation of COX-2, but not COX-1, in well-differentiated HCCs. The present study is the first to demonstrate a high expression of COX-2 in well-differentiated HCC and a low expression in advanced HCC, in contrast to its continuous expression during colorectal carcinogenesis. These findings suggested that COX-2 may play a role in the early stages of hepatocarcinogenesis, but not in the advanced stages, and may consequently be related to HCC dedifferentiation.

Intra-observer variation in the histopathological assessment of chronic viral hepatitis

Background/Aims: The way in which liver biopsies showing chronic hepatitis are reported is undergoing re-evaluation. A related question is how the inflammatory and fibrotic changes in these liver biopsies can be semi-quantitatively assessed so that comparisons can be made between groups of patients and the effect of treatment on disease progression studied. Methods: We have carried out a blinded trial in which 20 cases of chronic viral hepatitis were assessed by five histopathologists, using the Knodell and Scheuer scoring systems (two of the most commonly used systems), on two separate occasions. The results were analysed using Kappa statistics, and also by seeing for how many slides the pathologists showed no significant disagreement. Results: While both systems produced good inter- and intra-observer variation when fibrosis was assessed the Scheuer system produced slightly higher Kappa values. The Scheuer system produced considerably better agreement when the severity of inflammation was examined. A multirater kappa analysis confirmed that both systems showed better agreement for fibrosis scores than for inflammation scores. Conclusion: We conclude that, while both systems produced reasonable agreement, this was greater using the Scheuer system. When any new scoring system is being developed, the question of reproducibility needs active consideration.

Proliferative activity of hepatocytes in chronic viral hepatitis as revealed by immunohistochemistry for proliferating cell nuclear antigen

Liver biopsy specimens of 65 cases of chronic viral hepatitis, including 29 cases of type B, 34 cases of type C, and two cases of non-A, non-B, non-C type, were immunohistochemically stained for proliferating cell nuclear antigen (PCNA) to evaluate the proliferative acivity of hepatocytes. According to a histopathologic evaluation using the histology activity index (HAI) scoring system, chronic persistent hepatitis and chronic active hepatitis were clearly differentiated with no overlapping of the score. The labeling indices of PCNA of hepatocytes in chronic persistent hepatitis had a significant relationship with HAI scores ( r = .54), suggestive of a contribution of lobular hepatocyte necrosis and/or portal inflammation to the regenerative rate of hepatocytes, but did not exceed 3.0%. On the other hand, 11 of 47 cases of chronic active hepatitis showed PCNA labeling indices higher than 3.5% without any significant relationship with the HAI scores. There was no significant difference, however, of distribution of HAI scores or PCNA labeling indices between hepatitis types B and C. Based on current concepts of the role of hepatocyte proliferation in the development of liver cirrhosis and hepatocellular carcinoma, the present results suggest that the high proliferative rate of hepatocytes subject to the persistent liver cell injury in chronic active hepatitis may be related to a reconstruction pattern of the liver in cases of progression to cirrhosis and development of hepatocellular carcinoma.

Liver biopsy and the etiologic diagnosis of chronic hepatitis

The histological features of chronic viral hepatitis differ according to etiological agent and replicative phases. Thus, in chronic HBV hepatitis with a high level of HBV replication the histological lesion is generally mild. During the seroconversion phase, a lobular lesion is present in the liver biopsy followed by amelioration of the disease. Chronic delta hepatitis is very aggressive histologically, progression to cirrhosis is frequent, and sanded nuclei are often observed in liver biopsies of patients with anti-HIV. In contrast, chronic hepatitis C shows a milder histological picture and immunohistochemical techniques to detect HCV-Ag in the liver tissue should be developed. In summary, the majority of cases of chronic viral hepatitis have distinctive histological features that may be identified in liver biopsies.

Ratio of Serum Aspartate to Alanine Aminotransferase in Chronic Hepatitis Relationship to Cirrhosis

The ratio of the serum aspartate to alanine aminotransferase levels (AST/ALT) is often used as a clue to the etiology of the underlying liver disease. This ratio is usually >2.0 in alcoholic liver disease and <1.0 in patients with chronic hepatitis and chronic cholestatic syndromes. We analyzed the AST/ALT ratio in 177 patients with various forms of nonalcoholic chronic liver disease who underwent medical evaluation and percutaneous liver biopsy. In the majority of cases of chronic viral hepatitis, the AST/ALT ratio was <1.0. However, there was a statistically significant correlation between the AST/ALT ratio and the presence of cirrhosis. Among 100 patients with chronic type B hepatitis, the mean AST/ALT ratio was 0.59 in those without cirrhosis and 1.02 in those with cirrhosis. Furthermore, the AST/ALT ratio often rose to >1.0 when cirrhosis first became manifest. Thus, the finding of an AST/ALT ratio of >1.0 in a patient with nonalcoholic liver disease should suggest the presence of cirrhosis. In addition, the use of the AST/ALT ratio as a means of separating alcoholic and nonalcoholic liver disease must be tempered with the knowledge that this ratio may be less helpful in the presence of cirrhosis.

The Clinical Usefulness of Acth and Cortisone in Liver Disease

Summary It seems clear from the data presented that routine use of ACTH and cortisone is not indicated in any form of liver disease. The results to date with this therapy are unpredictable. From the present experience it seems likely that ACTH and/or cortisone are indicated in patients with acute hepatic disease of viral origin where jaundice is deep and sustained for several weeks. One can expect a rapid diminution of serum bilirubin in these patients. A trial of corticosteroid therapy is probably also indicated in patients with acute hepatitis who have suffered a spontaneous relapse of their disease. In the usual patient with viral hepatitis who remains jaundiced for 3 to 5 weeks, on the other hand, ACTH will probably not prove to be useful unless further studies demonstrate a significant shortening of the convalescent period by corticosteroids. The regular return of well-being and appetite and the continued improvement of liver function which have resulted from the use of ACTH and cortisone in certain cases of chronic viral hepatitis would seem to make a trial of these substances desirable, particularly in those cases where conservative therapy has failed. It should be remembered, however, that the sodium and water retention which result from the use of corticosteroids may complicate management to such a degree that one may be forced to withdraw the medication. Similarly in hepatic cirrhosis one may expect improvement of hepatic function under certain circumstances. In addition to the salt and water retention, the possibility of precipitating bleeding from esophageal varices should be considered. If it can be shown that the administration of large amounts of potassium will prevent sodium and water retention in patients with chronic liver disease, additional, perhaps more vigorous, trials of ACTH and cortisone will be warranted. A sudden withdrawal of corticosteroids may precipitate a relapse in any form of liver disease. On the other hand, administration of these substances has caused no demonstrable harm as far as the liver disease itself is concerned. The evidence favoring the use of ACTH and cortisone in hepatic coma has not been convincing. In view of the otherwise poor prognosis, however, the use of ACTH and cortisone as an adjunct to other measures may be indicated.