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Six patients with chronic liver disease and six sex-, age (+/- 5 years)-, and weight (+/- 5 kg)-matched healthy control subjects received a single dose of two 100 mg tablets rimantadine HCl. Eight additional patients with chronic liver disease who were not matched to healthy subjects received a single dose of two 100 mg tablets of rimantadine HCl. Blood and urine samples were collected and rimantadine concentrations were determined by a GCMS method. The values for maximum plasma concentration, AUC, elimination half-life, and renal clearance were not significantly different between patients and control subjects, independent of the statistical analyses (parametric and nonparametric) used. The mean apparent elimination half-life, volume of distribution, and total clearance in the matched patients with liver disease were 32 hours, 24 L/kg, and 676 ml/min, respectively. Renal clearance and the amount excreted in the urine unchanged were 63 ml/min and 10%, respectively. In conclusion, rimantadine pharmacokinetics were not appreciably altered in patients with less severe chronic liver disease.
Molecular events preceding the development of hepatocellular carcinoma were studied in the Mdr2-knockout (Mdr2-KO) mice. These mice lack the liver-specific P-glycoprotein responsible for phosphatidylcholine transport across the canalicular membrane. Portal inflammation ensues at an early age followed by hepatocellular carcinoma development after the age of 1 year. Liver tissue samples of Mdr2-KO mice in the early and late precancerous stages of liver disease were subjected to histologic, biochemical, and gene expression profiling analysis. In an early stage, multiple protective mechanisms were found, including induction of many anti-inflammatory and antioxidant genes and increase of total antioxidant capacity of liver tissue. Despite stimulation of hepatocyte DNA replication, their mitotic activity was blocked at this stage. In the late stage of the disease, although the total antioxidant capacity of liver tissue of Mdr2-KO mice was normal, and inflammation was less prominent, many protective genes remained overexpressed. Increased mitotic activity of hepatocytes resulted in multiple dysplastic nodules, some of them being steatotic. Expression of many genes regulating lipid and phospholipid metabolism was distorted, including up-regulation of choline kinase A, a known oncogene. Many other oncogenes, including cyclin D1, Jun, and some Ras homologues, were up-regulated in Mdr2-KO mice at both stages of liver disease. However, we found no increase of Ras activation. Our data suggest that some of the adaptive mechanisms induced in the early stages of hepatic disease, which protect the liver from injury, could have an effect in hepatocarcinogenesis at later stages of the disease in this hepatocellular carcinoma model.
Liver diseases can basically be categorised into the forms diffuse and focal. In case of diffuse liver diseases the damages in general affect the whole of the liver, but the alterations are usually present in varying degrees and severity. Relatively stereotypical reactions develop in the liver tissues on the effect of various damaging factors. Some of these reactions and their pathogenic backgrounds are well known, while others have only recently come into focus, like apoptosis and the regeneration-proliferation related hepatic stem cells. The number of damaging effects are naturally much higher than the number of possible response reactions and as a consequence, in many cases the etiological factors can not unambiguously be identified from the tissue alterations. The basic reaction types of the liver can be divided into well defined categories; thus adaptive changes, degeneration and intracellular storage, cell death (necrosis/apoptosis), inflammation, fibrosis and structural reorganisation, as well as regeneration/proliferation. The picture of "classic necrosis" is well known; with the detection of cellular swelling, membrane damage. Apoptosis is characterised by cell shrinkage, nuclear and cytoplasmic disruption, while the cell membrane remains intact. Apoptosis occurs in several liver diseases, with a striking form of appearance being the Councilman-like body seen in viral hepatitis. Apoptosis may have role in the pathogenesis of cholestasis, biliary atresia, the "vanishing bile duct syndrome", and alcoholic liver injury. The regenerative ability of the liver is excellent. The process is influenced by several growth factors and cytokines. In the case of chronic liver damage, however, the regeneration equilibrium becomes upset and irregular. Studies on liver regeneration have led to the recognition of hepatic stem cells. These cells of "oval" morphologic appearance are built up of a primitive structure, making them suitable for this task. Ductular proliferation originating from hepatic stem cells can mostly be recognised in three disease groups: liver regeneration following massive or submassive liver necrosis, ductular proliferation without liver insufficiency, and tumorous liver diseases. At present it is still unclear whether the hepatocyte formation originating from haematopoetic stem cells is a rarely occurring accidental transformation, or rather, under appropriate circumstances, a greatly effective "third" protective system. If the latter is true, this can fundamentally change our view on the pathomechanism of liver diseases, making possible numerous novel therapeutic treatments.
184 autopsy cases with liver diseases were examined clinicopathologically with special reference to the incidence and distribution of microthrombi and classic thrombi in various organs. Microthrombi and/or classic thrombi were found in one or more organs in 50.0% to 59.4% of the patients with various liver diseases. But only 4 among 184 patients had many microthrombi in more than three organs and the incidence of disseminated intravascular coagulation seemed to be low in autopsy cases with liver diseases. Incidence of microthrombi showed no significant difference in the groups with and without portal vein thrombosis. Hemorrhage in the upper alimentary tracts of the patients with liver cirrhosis did not seem to develop by disseminated intravascular coagulation. Consumption of clotting factors in liver diseases seemed to occur by thrombus formation in portal vein and esophageal varices and by hemorrhage in various organs.
Patients with underlying liver disease have an increased surgical risk. Prediction of surgical risk is based on the degree of liver dysfunction, the type of surgery, and the preoperative clinical status of the patient. The medical consultant must determine the type of liver disease (acute or chronic) and the degree of impairment of liver function (based on physical examination and laboratory data). Any abnormalities should be corrected prior to surgery. Elective surgery should be postponed in patients with decompensated cirrhosis (class B and C) and acute hepatitis until the patient improves. The consultant internist's care of the patient should continue during the early postoperative course to monitor any deterioration in liver function.
The study of chronic liver disease has been hampered by insufficient information relative to the pathogenesis of the many forms of hepatitis. Consequently, well-designed treatment strategies are frequently lacking. Wilson's disease is characterised by excessive copper accumulation in the liver and other organs. While d-penicillamine is clearly effective, many patients may not tolerate its many adverse effects. Trientine, oral zinc and unithiol have all shown promise as therapeutic alternatives. Autoimmune chronic active hepatitis responds well to prednisone and azathioprine. Cyclosporin has also produced clinical improvement in several case reports but no comparison has yet been made with the current standard therapy. Recombinant interferon-alpha (IFN alpha) has demonstrated the ability to inhibit hepatitis B viral replication, and the combination of oral corticosteroids followed by IFN alpha is more effective than either agent alone in eliminating viral replication in patients with chronic active hepatitis B. Currently, primary sclerosing cholangitis (PSC) has no standard medical management, but corticosteroids and methotrexate may each have a future role in its treatment. Drug treatment for primary biliary cirrhosis (PBC) has been disappointing, and early reports of success with d-penicillamine were not confirmed in large well-controlled trials. While some reports of improvement with several agents have been described, larger studies are still needed. Alcoholic liver disease continues to be associated with significant morbidity and mortality and numerous investigators have researched several different medical avenues of treatment. Success reported with androgens and the antithyroid agent propylthiouracil in alcoholic liver disease will need confirmation by other research before these agents can be recommended for routine use. Finally, colchicine may prove to be effective in slowing the rate of fibrosis in cirrhosis, but this has yet to be conclusively proven.
Monooxygenase enzymatic activities were measured in liver and kidney microsomes of control and ethanol-treated rats. Animals were administered alcohol by using a model for alcoholic liver injury. Several in vitro approaches were used to compare the laurate metabolism in liver and kidney microsomes: correlation studies between specific P-450 catalytic activities, immunoblot analysis, and chemical and immunoinhibitions. Ethanol treatment increased the liver and renal hydroxylations of chlorzoxazone and 4-nitrophenol. Moreover, lauric acid (omega-1)-hydroxylation was found to be significantly increased (-6-fold) after ethanol treatment in liver, but not in kidney microsomes. The laurate omega-1/omega ratio increased from 1.52 +/- 0.49 to 4.11 +/- 1.01 in liver microsomes of control and ethanol-treated rats, and from 0.29 +/- 0.06 to 0.44 +/- 0.07 in kidney microsomes. Immunoblot analysis using polyclonal anti-cytochrome P-450 (CYP) 2E1 or CYP4A antibodies showed an increase of CYP2E1 and CYP4A contents in both organs, but the increase was higher in liver than in kidney microsomes. Chemical inhibitions using CYP2E1 competitive inhibitors (such as chlorzoxazone and ethanol) led to a nonsignificant inhibition of the renal (omega-1)-hydroxylation of lauric acid. In contrast, 17-octadecynoic acid (a mechanism-based inhibitor of omega-hydroxylase) was able to inhibit both omega- and (omega-1)-hydroxylations of lauric acid in kidney microsomes. Immunoinhibitions specific to CYP2E1 significantly decreased the (omega-1)-hydroxylation of lauric acid in liver, but not in kidney microsomes, whereas the polyclonal anti-CYP4A1 antibody inhibited omega- and (omega-1)-hydroxylations of lauric acid in kidney microsomes. All of these results show that lauric acid hydroxylations in liver and kidney respond in different manners to ethanol treatment. Lauric acid (omega-1)-hydroxylation, a highly specific probe for CYP2E1 in rat and human liver microsomes, is mediated by a CYP4A isoform in rat kidney microsomes.
Liver disease with inclusions of copper was recognized among 30 rural workers with "vineyard sprayer's lung." The pathological findings were varied: focal or diffuse swelling and proliferation of Kupffer cells; histiocytic and sarcoid-like granulomata; fibrosis of variable degree in the perisinusoidal, portal, and subcapsular areas, accompanied by atypical proliferation of the sinusoidal lining cells; micronodular cirrhosis; angiosarcoma of the liver; idiopathic portal hypertension. Abundant deposits of copper were revealed by histochemical techniques within hepatic and pulmonary lesions in these patients. The observations on the human and experimental material suggest an etiological relationship between exposure to copper sulfate and the lesions described. A morphological resemblance was noted between the "liver disease of vineyard sprayers" and the hepatic lesions reported in workers exposed to inorganic arsenic and to vinyl chloride. The identification of the inhaled foreign material within the liver lesions raises important etiological considerations.
In our country liver diseases are frequent and have many different causes. They can often develop into cirrhosis of the liver with mortality beetween 13.5% and 24.5%. Hepatitis B and C-viral infections frequently play a significant role in the recognition of an occupational disease in the case of medical staff, with histological criteria of major importance in this respect. A consequence of cirrhosis of the liver may be the development of hepatoencephalopathia of varying degrees of severity. As it is then likely that a patient will no longer be able to drive motor vehicles, it is important that attending physicians inform their patients accordingly. Liver transplants are an acknowledged method of treatment in the therapy of advanced liver cirrhosis. Rehabilitation shortly after transplantation is highly important to help ensure a speedy return to work. Surprisingly, reintegration is more difficult in patients suffering from alcohol related liver disease than in those with non-alcohol-related liver disease.
To make liver biopsy unnecessary in certain cases, PGA (P, prothrombin time; G, gamma-glutamyl transpeptidase; A, apoliprotein AI), a simple biological index combining a specific test for severe liver disease (prothrombin time), a sensitive test of alcoholic liver disease (serum gamma-glutamyl transpeptidase), and a test for liver fibrosis (serum apolipoprotein AI), was evaluated in a training sample of 333 drinkers and validated in 291 other drinkers. All patients underwent an intercostal liver biopsy, and the specimen was independently read by two pathologists. The PGA index varied from 0 to 12. When PGA was less than or equal to 2, the probability of cirrhosis was 0% and the probability of normal liver or minimal changes 83%. Conversely, when PGA was greater than or equal to 9, the probability of normal liver or minimal changes was 0% and the probability of cirrhosis 86%. These values did not vary between training and validation periods, between asymptomatic vs. symptomatic subjects or between PGA at admission vs. PGA 1 week later. This index could be useful for general practitioners in identifying subjects at high risk for severe alcoholic liver disease.
Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.
Disseminated intravascular coagulation (DIC) and liver diseases are complex clinical conditions. Both disorders frequently disturb the finely tuned coagulation and fibrinolysis equilibrium. In DIC, a wide range of underlying disorders can induce a systemic activation of the coagulation system with generation of soluble fibrin, possible deposition of platelet-rich fibrin clots in the microvasculature and subsequent micro- or macroembolism, impaired organ perfusion and organ failure. Such coagulation activation depletes platelets, coagulation factors, and inhibitors and clinically can result in severe, sometimes untreatable bleeding, especially when bone marrow or liver function is diminished or invasive procedures are performed. In addition, a secondary counterbalancing activation of the fibrinolytic system to dissolve microcirculatory clots adds to the bleeding tendency. In conjunction with other options based on prompt and rigorous treatment of the underlying cause of DIC, fresh frozen plasma plays an important role in therapeutic management when overt bleeding is present or anticipated in DIC patients with disturbed coagulation or when an invasive procedure is being planned. In liver disease, factor and inhibitor synthesis in both the coagulation and fibrinolytic system is impaired, both quantitatively and qualitatively. This destabilizes the balance between the two systems. In addition, the clearance of activated coagulation factors and fibrin(ogen) degradation products (FDP) from the systemic circulation is impaired. In patients with liver diseases and acute or imminent bleeding, or before invasive procedures, fresh frozen plasma (FFP) offers advantages over clotting factor concentrates. However, hypervolemia following the required doses of FFP might pose a problem in some liver disease patients.The complex pathophysiology both in DIC and in liver disease requires early diagnosis and adequate management including plasma and platelet substitution after treatment of the underlying disease. Due to the heterogeneity of DIC and liver disease, prospective randomized trials are difficult to perform. Therefore, treatment recommendations are mostly empirical and less evidence-based. Therapy must be accompanied by close and repeated clinical and laboratory monitoring.
One hundred sera samples, obtained during the early postoperative period from 11 patients after a partial hepatectomy, were assayed for alpha-fetoprotein (AFP). None were AFP-positive by radioimmunoassay, despite clinical and biochemical recovery associated with normal liver regeneration. AFP was elevated in 29% of patients with acute hepatitis, 34% of patients with chronic active hepatitis, and in 75% of patients with massive hepatic necrosis. The mechanism and significance of AFP elevations in some patients with acute and chronic hepatitis is uncertain but probably does not reflect normal liver regeneration.
Complications of chronic liver diseases requiring surgical interventions are the following: esophageal varices and bleeding, ascites hypersplenism, some forms of liver insufficiency. The most widely accepted method for treatment of esophageal varices is endoscopic sclerotherapy. Portal systemic shunts are indicated in some cases. Intractable ascites is to be treated by peritoneovenous shunt insertion. "Ressissance" of paracentesis is not confirmed by late results. Splenectomy is proposed if clinical signs are prominent. If portal hypertension exists, shunt should be performed simultaneously. Liver transplantation is indicated in cases of irreversible liver damage. Optimal selection of patients and timing of transplantation remains of critical importance. As a consequence of numerous technical modifications liver transplantation becomes more popular. Statistical data on liver diseases in Hungary call for urgent development of hepatology. Cooperation of physicians is of outmost importance to realize it.
Imaging methods in liver diseases. The author reviews the diagnostic imaging procedures applied most commonly in liver disease in this day and age- with special attention to ultrasound imaging. She describes the possibilities, performance and disadvantages of the imaging procedures. She makes a recommendation for a generally applicable optimal investigative sequence.
Serum levels of carbohydrate-deficient transferrin (CDT) were assayed in 87 patients with alcoholic liver disease, 25 alcoholics without liver disease, 25 cases with viral liver disease and 37 healthy subjects, by two different methods (Pharmacia CDT RIA kit and Axis % CDT kit). The serum level of Pharmacia-CDT was significantly higher in the patients with alcoholic liver disease (38.9 +/- 2.8 U/l) compared to the normal subjects (18.9 +/- 0.2 U/l), alcoholics without liver disease (21.7 +/- 1.5 U/l) and non-alcoholic liver disease (viral liver disease) (23.4 +/- 1.6 U/l) (P < 0.001). The serum level of Axis-CDT was also significantly higher in the patients with alcoholic liver disease (4.22 +/- 0.48%) compared to the normal subjects (0.84 +/- 0.14%), alcoholics without liver disease (1.14 +/- 0.23%) and non-alcoholic liver disease (1.84 +/- 0.29%) (P < 0.001). A significant correlation was found between serum levels of CDT determined by the two kits (r = 0.718, P < 0.001). The serum level of Axis-CDT was significantly higher in patients with alcoholic hepatitis compared to the normal subjects (P < 0.005), while the serum level of Pharmacia-CDT was not increased in the patients with alcoholic hepatitis. These results indicate that determination of serum CDT levels is a useful marker of alcoholic liver disease, not a marker for alcohol consumption. Axis-CDT is more useful than Pharmacia-CDT for assaying the serum level of CDT in patients with alcoholic liver disease.
Circulating immune complexes have been described in most liver diseases, including alcoholic liver disease, although their pathogenic significance remains unclear. Currently available immune complex assays do not distinguish immunoglobulin aggregates from antigen-antibody complexes. Immunoglobulin aggregate formation occurs in vitro at 37 degrees C in the presence of hypergammaglobulinemia and/or hypoalbuminemia, conditions common in liver disease. To determine if hypergammaglobulinemia and/or hypoalbuminemia could predispose to immunoglobulin aggregate formation in vivo, 25 patients with alcoholic liver disease were studied. Using sucrose density gradient fractionation followed by quantitation of IgG by radioimmunoassay, high molecular weight IgG complexes (greater than 11S) were frequently present in alcoholic liver disease sera, and correlated with the degree of hypergammaglobulinemia and/or hypoalbuminemia, and with 125I-C1q binding activity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of these complexes revealed only IgG and nonspecific trapping of several normal serum proteins. A specific complex-associated antigen could not be identified. While small, undetectable quantities of true antigen-antibody complexes might also be present, our data suggest that IgG complexes in alcoholic liver disease may represent immunoglobulin aggregate formation in vivo.