Plasmapheresis in the treatment of hepatic coma]

Fourteen patients, including 6 with viral hepatitis B and 8 with liver cirrhosis were treated with plasmapheresis for hepatic coma. Altogether 29 plasmaphereses were carried out. Complete recovery was achieved in one patient with viral hepatitis B and in 3 patients with liver cirrhosis. Plasmapheresis should be performed in patients with severe lesions to the liver. Classification of patients to the treatment should include clinical examination, biochemical and enzymatic tests, and evaluation of liver reserve with isotope hepatography. In case of the acute poisoning with hepatotoxic agents indications to plasmapheresis should be evaluated from the toxicologic point of view.     

A Clinical Evaluation of Peritoneal Dialysis

A total of 18 peritoneal dialyses were performed on 14 patients at the Hamilton Civic Hospital over a period of 11 months. Nine of these patients were in uremia, four had non-nephrotoxic intoxication, and one had hepatic coma. Patients with chronic uremia may present with acute renal failure which may be treated by peritoneal dialysis with resultant significant prolongation of life. A decreased mortality rate might be expected in acute renal failure if dialysis is implemented before the classical picture of uremia develops. Many non-nephrotoxic intoxicating substances are readily dialysable. Considerable benefit to the patient and decreased time in hospital may result from the use of this procedure in cases of intoxication with such substances. Peritoneal dialysis may be of value in treatment of intractable congestive heart failure. This procedure may eventually provide another means of treating hepatic coma.     

Acute Hepatic Coma Successfully Treated by Extracorporeal Baboon Liver Perfusions

Two patients in deep hepatic coma due to fulminant viral hepatitis were treated by extracorporeal baboon liver perfusion after failing to respond to medical treatment and three consecutive exchange transfusions. Both patients recovered full consciousness after one liver perfusion, made a complete recovery, and were leading normal lives seven and eight months after treatment. Perfusions were maintained for 13½ and 16½ hours without complication, and neither clinical immunological reactions nor antibaboon serum antibodies developed as a result of treatment.Whereas normal consciousness could be restored only by liver perfusion, both exchange transfusion and liver perfusion were effective in clearing bilirubin and in raising the level of clotting factors. Extracorporeal baboon liver perfusion provides a safe and effective method for the treatment of acute hepatic coma.     

Prostacyclin synthesis stimulating plasma factor in patients with different stages of hepatic coma

In patients with acute hepatic coma the prostacyclin synthesis stimulating plasma factor is significantly enhanced. This increased activity has been verified by using various test systems. However, there is no correlation between the actual plasma factor activity and the coma stage, respectively. The increase of plasma factor activity in these patients might account at least in part for the increased bleeding tendency seen in these patients.     

Degradation of prostacyclin in the plasma of patients with terminal liver insufficiency

It has been suggested earlier that the increased bleeding tendency observed in patients with hepatic coma is due to prostaglandin I₂. Various experimental studies have reported an increased prostaglandin I₂-formation, an enhanced plasma factor activity and a prolonged synthesis in-vitro. However, the rate of degradation of prostaglandin I₂ in plasma could be another determinant alterating the locally available biologically active substance but this has not been examined so far. Thus, we examined the half-life of synthetic prostaglandin I. in-vitro in plasma from 25 patients with terminal liver insufficiency in different stages of hepatic coma. In 8 healthy volunteers a 6 months follow up shoed no significant change. The half-life of prostaglandin I. in controls was 10.21 ± 2.70 minutes, no different from coma stage I. (10.16 ± 1.36 minutes), coma stage II (10.86 ± 2.24 minutes), coma stage III (10.95 ± 3.06 minutes) or coma stage IV (12.07 ± 2.88 minutes). However, a modest trend towards a prolongation and an increase in standard deviation with the coma stage can be noted. No influence of various drugs commonly used in these patients could be seen. It can thus be concluded that there is no important difference in degradation speed fo prostaglandin I₂ in the plasma of patients with terminal liver insuffiency, which could account for the increased bleeding tendency.     

Renal failure in otherwise uncomplicated acute viral hepatitis.

Twelve patients with otherwise uncomplicated acute viral hepatitis (two were HBsAg-positive) developed renal failure. Apart from dehydration due to repeated vomiting in one patient, no factor responsible for precipitating renal failure could be identified. The clinical course was characterised by renal failure with plasma urea concentrations reaching maximum values of 26-69 mmol/l (175-416 mg/100 ml). Ten patients needed dialysis for up to two weeks. Seven patients recovered completely, while the other five died from sepsis. The types of renal failure were similar to those described in fulminant hepatic failure and cirrhosis--namely, functional renal failure in five patients and acute tubular necrosis in seven. Two of the patients with functional renal failure later developed tubular necrosis. The mechanism responsible for renal failure in acute viral hepatitis is uncertain, though endotoxaemia may contribute.     

Correlation between serum enzymes and serum unsaturated vitamin B12 binding proteins in primary liver carcinoma

The serum unsaturated vitamin B12-binding capacity (UBBC), unsaturated transcobalamin (UTC) I, UTC II, UTC III levels, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activities and bilirubin concentration were estimated in 61 patients with liver diseases (31 with hepatoma, 30 with viral hepatitis). The levels of serum cobalamin, UTC I, UTC III, UBBC, alanine and aspartate aminotransferases, and bilirubin were raised in both hepatoma and viral hepatitis patients. Serum UTC II was reduced in both conditions. Alkaline phosphatase activity was significantly increased in hepatoma. Four significant correlations were observed among these parameters in the hepatoma patients while only one significant correlation was observed in viral hepatitis.     

Metabolism of thyroxine in acute viral hepatitis

Aim of this report was to define the correlation between hepatic acute damage and thyroxine metabolism. We have studied plasma levels of T4, T3, rT3 and TSH in 18 adult male subjects with acute viral hepatitis. No significant variation of T4, T3 and TSH plasma levels was found in different phases of disease. However, plasma rT3 levels were clearly elevated in 72% of patients in the first 7 days (mean 440 pg/ml vs 198 pg/ml of normal controls) and in 17% of cases in the second 10 days of disease (mean 269 pg/ml). Plasma rT3 concentration was always normal in the subsequent phases of disease. Our results indicate a diversion of peripheral thyroxine metabolism in the early stages of acute hepatitis.     

Decreased vascular endothelial growth factor response to acute hypoglycemia in type 2 diabetic patients with hypoglycemic coma

IntroductionPlasma vascular endothelial growth factor (VEGF) was shown to increase during acute hypoglycemia and could mediate rapid adaptation of the brain. In this study we examined the neuroendocrine response in patients with type 2 diabetes mellitus (T2DM) in hypoglycemic coma or with acute neuroglycopenic symptoms.MethodsWe prospectively studied 135 consecutive T2DM patients admitted for severe hypoglycemia during a 2-year period. We collected clinical variables and measured plasma concentrations of VEGF, epinephrine, norepinephrine, cortisol and growth hormone at admission and 30 min afterwards.ResultsThirty two patients developed hypoglycemic coma and 103 did not lose consciousness. Median plasma VEGF level of coma patients was 3.1-fold lower at baseline than that of non-coma patients, and even 5.3-fold lower 30 min afterwards. Plasma epinephrine concentration was significantly lower just at baseline in coma patients. On the contrary, there were no differences in concentrations of the other hormones. Multivariate logistic regression analysis showed that VEGF concentration (OR 0.68; CI 0.51–0.95) was a protective factor against the development of coma.ConclusionsVEGF and epinephrine responses to acute hypoglycemia are reduced in T2DM patients who develop hypoglycemic coma. An increased plasma VEGF concentration appeared to be a protective factor against the development of hypoglycemic coma.     

Elevation of liver-galactosylhydroxylysyl glucosyltransferase activity in human primary hepatocellular carcinoma

The activity of L-GGT (EC 2.4.1.66), an enzyme catalyzing the intracellular biosynthesis of collagen, was determined in human primary hepatic cancer, acute viral hepatitis and cirrhotic liver tissues and compared to the mean level of enzyme activity in normal human liver tissues. The mean levels of L-GGT activity in primary hepatocellular carcinoma (PHC), acute viral hepatitis and cirrhotic tissues were 7.78, 2.69 and 2.16 times the mean level of enzyme activity in normal human liver tissues. The mean level of L-GGT activity in PHC was 3.61 times the mean level of L-GGT activity in cirrhosis and 2.90 times the mean value of liver enzyme activity in acute viral hepatitis. The findings in this study provide a basis for the highly elevated serum values of this intracellular enzyme in patients with primary hepatic cancer and the data indicate that L-GGT activity may be increased in primary liver cancer to compensate for an increased rate of collagen synthesis.     

CORRELATION OF PLASMA AND BRAIN AMINO ACID AND PUTATIVE NEUROTRANSMITTER ALTERATIONS DURING ACUTE HEPATIC COMA IN THE RAT

During acute hepatic coma following two-stage hepatic devascularization in the rat, profound changes occurred in plasma and whole-brain amino acids and putative neurotransmitters. Brain ammonia, glutamine and GABA were increased, aspartate was decreased, while glutamate was unchanged. An increase in brain tryptophan was accompanied by a similar increase in plasma unbound tryptophan but decreased plasma total tryptophan. These changes occurred in the presence of high plasma levels of the other neutral amino acids, including the branched chain amino acids. Plasma insulin was unchanged while glucagon levels rose, resulting in a decreased insulin to glucagon ratio. These results suggest that while plasma unbound tryptophan may influence brain tryptophan levels, altered plasma concentrations of neutral amino acids which compete with tryptophan for transport into the brain do not contribute to the increase in brain tryptophan observed during acute hepatic coma.     

A double-blind evaluation of transfer factor therapy of HBsAg-positive chronic aggressive hepatitis: preliminary report of efficacy.

A controlled, prospective, double-blind trial of transfer factor in chronic aggressive hepatitis was carried out. This report presents the results obtained from study of the nine HB_sAg-positive subjects who were included in the trial. Transfer factor was prepared from adults who had recovered from acute hepatitis B or from acute non-B viral hepatitis and was administered to five HB_sAg-positive subjects. Four HB_sAg-seropositive subjects received placebo. Percutaneous liver biopsy was performed at the beginning and at the conclusion of the 10-week study period; biochemical and clinical parameters were monitored throughout. Cell-mediated immunity was assessed at the beginning and at the end of the study period. Four of five transfer factor recipients showed moderate or marked improvement in hepatic histology, clinical status, and serum transaminase levels, while none of four placebo recipients demonstrated improvement. The difference in response between the two groups was significant (P = 0.048). No consistent changes in in vivo or in vitro correlates of cell-mediated immunity were demonstrated. No adverse effects were noted among transfer factor recipients. These data suggest that transfer factor may be of benefit in chronic aggressive hepatitis associated with HB_sAg. Additional studies appear to be indicated to delineate the mode of action of transfer factor as well as the role that such immunotherapy should play in the management of patients with this disorder.     

Plasma transforming growth factor beta1, metalloproteinase-1 and tissue inhibitor of metalloproteinases-1 in acute viral hepatitis type B

AIM: Antiproliferative, pro-apoptotic and immunosuppressive activity effects suggest crucial role of transforming growth factor (TGF)-beta1, metalloproteinase (MMP)-1 and its tissue inhibitor (TIMP)-1 in the pathogenesis of acute liver injury that in some patients precede development of chronic liver diseases and fibrogenesis. The aim of this study was to evaluate effect of acute HBV infection on plasma TGF-beta1, MMP-1 and TIMP-1 levels. METHODS: TGF-beta1, MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 39 patients with acute viral hepatitis type B. Baseline measurement was performed within the first week of jaundice and then weekly up to the fourth week of the disease. Results were compared to baseline and normal values and to liver function tests. RESULTS: Plasma concentrations of TGF-beta1, TIMP-1 and MMP-1 were significantly elevated in the first week of acute viral B hepatitis in comparison to normal. Analysis of individual values demonstrated significant positive correlation between plasma concentrations of TGF-beta1 and TIMP-1. There was no correlation between MMP-1 and TGF-beta1 or TIMP-1. Significant correlation was demonstrated between both TGF-beta1 and ALT or AST as well as between TIMP-1 and ALT, AST or bilirubin. Elevated baseline levels of both TGF-beta1 and TIMP-1 decreased gradually in consecutive weeks of the disease. TGF-beta1 but not TIMP-1 plasma concentrations were significantly lower in 3rd and 4th week than baseline values. MMP-1 concentration remained on baseline level in the 2nd week of the disease. However in the 3rd week its values increased suddenly but the significant difference in comparison to baseline was observed only in 4th week. CONCLUSIONS: These results indicate important role of TGF-beta1, TIMP-1 and MMP-1 in acute viral hepatitis, that seems to be connected first of all with hepatocytes damage. Their role in extracellular matrix metabolism during acute liver injury needs further evaluation.     

Respective Roles of Ammonia, Amino Acids, and Medium-Sized Molecules in the Pathogenesis of Experimentally Induced Acute Hepatic Encephalopathy

Ammonia, amino acids (AA), and middle molecules (MM) have been implicated in the pathogenesis of experimentally induced acute hepatic coma in the pig. Hemodialysis (HD) using either a low- (Cuprophan = CU) or a high-permeability (polyacrylonitrile = AN 69) membrane has demonstrated the role of MM. Selective hemodialysis (SHD) of AA or NH3 and MM was performed by adding either NH3 (group I) or AA (group II) to the dialysate during AN 69 HD; for MM, SHD only was performed by adding NH3 and AA to the dialysate (group III). In group I the brain levels of tyrosine were similar to those in undialyzed animals with decreased striatal dopamine and decreased norepinephrine in the midbrain only. Brain tryptophan was higher than normal, but brain levels of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid (5-HT, 5-HIAA) were within normal limits. In group II, despite an efficient NH3 clearance, brain NH3 levels were as high as in group I and did not correlate with plasma levels. Brain tyrosine (despite tyrosine overload of the dialysate) was lower than in group I; striatal dopamine decreased (but to a lesser extent than in group I), and norepinephrine was normal. Brain tryptophan was higher than normal, with an increase in brain 5-HT and 5-HIAA. In group III, results were similar to group I, except for a limited increase of 5-HT in the pons. Brain octopamine levels increased only in undialyzed and CU-HD animals, demonstrating a specific relation with MM. These experiments demonstrate the interrelationship between NH3 and neutral AA with regard to passage through the blood-brain barrier and to intracerebral metabolism.     

Brain Quinolinic Acid in Chronic Experimental Hepatic Encephalopathy: Effects of an Exogenous Ammonium Acetate Challenge

Abstract: Elevated brain concentrations of the neurotoxin and NMDA receptor agonist quinolinic acid (QUIN) have been demonstrated in portacaval-shunted (PCS) rats, a chronic hepatic encephalopathy (HE) model. Increased brain QUIN levels have also been shown in acute hyperammonemic rats. In the present study, the plasma and brain (neocortical) QUIN levels in chronic PCS rats were investigated. The study also included a single exogenous ammonium acetate (NH₄Ac; 5.2 mmol/kg, i.p.) challenge to precipitate a reversible hepatic coma. Compared with sham-operated controls, chronic PCS rats exhibited decreased rather than increased plasma and brain QUIN levels. The plasma-to-brain QUIN ratio was not found to be altered. The NH₄Ac administration induced coma in all of the PCS rats 20–25 min after the challenge, and this coma was resolved within 60–75 min. No relevant temporal relationship between changes in brain QUIN levels and the neurological status in the PCS rats was observed. Therefore, our results do not support the contention that increased brain QUIN levels per se are involved in the pathogenesis of HE.     

Association study of the Ile50Val polymorphism of interleukin-4 receptor gene (IL4RA) with chronic viral hepatitis

The study was performed to estimate association of the Ile50Val polymorphism in IL4RA and clinical characteristics of chronic viral hepatitis including course of disease manifestation which is determined by degree of hepatic fibrosis. The group under investigation included 61 patient diagnosed with chronic viral hepatitis. Control group consisted of 128 randomly selected inhabitants of Tomsk city. Genotyping of Ile50Val polymorphism in the groups was performed by RFLP (restriction fragment length polymorphism) analysis. There was no significant differences in genotypes and alleles frequencies between cases and controls. However differences in genotype distribution depend on fibrosis stage were detected. Ile/Val heterozygote frequency in subgroup of patients without hepatic fibrosis was lower (7.1%) than in controls (51.6%) (p = 0.002) due to increase of both homozygote classes. Subgroup of patients without hepatic fibrosis differed by genotype frequencies both from patients with moderate and severe disease stage (p = 0.035; p = 0.004).     

Tracking hepatitis C virus quasispecies major and minor variants in symptomatic and asymptomatic liver transplant recipients.

To evaluate the possibility that distinct viral quasispecies play a role in the pathogenesis of progressive hepatitis C virus (HCV) infection, we performed a detailed evaluation of HCV quasispecies before and after liver transplantation in five patients infected with HCV genotype 1, three of whom developed severe recurrent hepatitis C and two of whom developed asymptomatic posttransplant infections with high-titered viremia. HCV quasispecies were characterized by using a combination of nucleotide sequencing plus heteroduplex tracking assay of the second envelope gene hypervariable region (HVR). An average of 30 HVR clones were analyzed per specimen; an average of five specimens were analyzed per patient over a 6- to 24-month study period. The complexity of HCV quasispecies in pretransplant serum varied, ranging from one to nine genetically distinct variants for the five patients. However, in all five cases, relatively homogenous quasispecies variants emerged after liver transplantation. In the three patients who developed recurrent hepatitis, quasispecies major variants present in pretransplant serum were efficiently propagated immediately after liver transplantation and were propagated throughout the course of acute and chronic hepatitis. In contrast, in the two asymptomatic cases, we observed rapid depletion of pretransplant quasispecies major variants from posttransplant serum, followed by emergence of new quasispecies variants by posttransplant day 30. Genetic analysis suggested that in these cases, the new quasispecies variants were derived from minor variants present at relatively low clonal frequency (less than 5% of HVR clones) within the pretransplant quasispecies populations. These data demonstrate that quasispecies tracking patterns are associated with the rapidity and severity of HCV-associated liver disease after liver transplantation. Further characterization of HCV quasispecies in animal model systems is warranted.     

Klatskin tumor--results of surgical therapy

Between January 1st 1990 and December 31st 1999, 24 patients affected by Klatskin tumor underwent operation in our department of surgery. According to Bismuth's classification, there were 0 (0%) type I, 5 (21%) type II, 6 (25%) type IIIa, 4 (17%) type IIIb and 9 (37%) type IV tumors. Five patients (21%) were treated by curative resection (group I) while in 14 patients (58%) palliative surgical procedure was performed (group II). In 5 cases (21%) the extension of malignancy did not allowed any procedure (group III). Curative resection for malignant tumors of the hepatic duct bifurcation included wide tumor excision and bile duct resection at the liver hilum (with wedge hepatic resection in one patient) and creation of biliary-enteric anastomosis. Palliative surgical procedure included stent insertion. Jaundice was completely relieved in all patients undergoing resection, since 3 patients (21%) after stenting hadn't satisfactory biliary drainage. There was 1 (20%) perioperative death in the group 1, while in group 2, 5 patients (36%) died postoperatively. In this series, the mean postoperative survival of all patients was 16 months. The mean postoperative survival of patients undergoing localized tumor resection with curative intent was 38 months, in contrast to 10 months for those undergoing operative stent insertion. in addition, only 1 patient from group III, in whom only exploratory surgery were performed survived 7 months, while other 4 patients died in the hospital. This retrospective review suggests that aggressive surgical treatment could improve survival and quality of life in patients suffering from Klatskin tumor.     

Evaluation of serum guanase in hepatic diseases

Serum guanase activity was measured in 20 healthy adults and in 62 patients with acute viral hepatitis, chronic active hepatitis, chronic persistent hepatitis, liver cirrhosis and fatty liver. Guanase and gamma-GT in patients were elevated in 87 and 64%, respectively. Elevated guanase activities were found in most cases of acute viral hepatitis, as well as in chronic hepatopathies. In patients with acute viral hepatitis pathologic activities of guanase were found following partial or total normalization of other liver function tests.     

Prevalence of viral hepatitis among the hospital staff in CSR between 1980 and 1982

The hepatitis morbidity data were used to study prevalence rate of manifest viral hepatitis among the hospital staff members in CSR over a 3-year period between 1980 and 1982. This study showed that the overall hepatitis morbidity rate was 2.68 per 1,000 health personnel and was 3.6 times as high as that recorded in a normal population matched by age. The mean HBsAg positivity rate was 1.67 per 1,000 and was 5.8 times the rate in the control population group. The rate of HBsAg-negative cases of hepatitis was 1.01 per 1,000 health personnel and was higher than double the rate of morbidity encountered in an age-matched normal population. The highest morbidity rates were recorded in the lower-grade and auxiliary health personnel. When compared with an age-matched normal population the hospital staff members at all departments had distinctly higher morbidity rates than the general population, but the highest risk of acquiring viral hepatitis was evidently run by the personnel at departments of renal dialysis, biochemistry, hematology, infectious diseases, internal medicine, surgery, urology and TRD (tuberculosis and respiratory diseases). Of a total number of recorded cases of viral hepatitis those with HBsAg positivity predominated, especially at departments of urology, TRD, internal medicine, renal dialysis, psychiatry and hematology. Analyzed by specialty and professional status of personnel these viral hepatitis morbidity rates encountered among the hospital staff members seem to point to at least two conclusions: this infection in the health personnel is work-related and its transmission and spread is dependent on the frequency and intensity of contact with the blood and other secretions of infectious patients.