Liver Disease and Cirrhosis

Cirrhosis occurs most frequently in the setting of alcoholic liver disease and represents the final common pathway of a number of chronic liver diseases. The development of cirrhosis is characterized by the appearance of fibroblasts and collagen deposition. This is accompanied by a reduction in liver size and the formation of nodules of regenerated hepatocytes. As a result, total liver content of cytochrome P450 is reduced in these patients. Initially, fibroblasts deposit collagen fibrils in the sinusoidal space, including the 

When portosystemic shunting is present total hepatic blood flow (Q) equals the sum of perfusion flow (Q ) and shunt flow (Qs). Portocaval shunting will impair the efficiency of hepatic extraction and reduce the extraction ratio as indicated by the following modification of Equation 7.5 (23). 

The corresponding impact on hepatic clearance is given by the following equation  

Because Q and Qp are both reduced in patients with severe cirrhosis in whom portocaval shunting is most pronounced/ hepatic clearance will be reduced more for nonrestrictivefy than for restrictively metabolized drugs. 

Similarly/ restrictively metabolized drugs exhibit little first-pass metabolism even in patients with normal liver function/ so portocaval shunting will have little impact on drug bioavailability. On the other hand/ portocaval shunting will decrease the extraction ratio and increase the bioavailability of nonrestric-tively metabolized drugs as follows  

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Cirrhosis is the result of long-term insult to the liver, so damage is typically not evident clinically until the fourth decade of life. Chronic liver disease and cirrhosis combined were the 12th leading cause of death in the United States in 2002. In patients between the ages of 25 and 64, damage from excessive alcohol use accounted for over one-half of the deaths.2 Alcoholic liver disease and viral hepatitis are the most common causes of cirrhosis in the United States and worldwide. 

Cataracts in early childhood 1 1 Cataracts often within a few days of birth Vomiting and diarrhea after milk ingestion Jaundice and hyperbilirubinemia Hypoglycemia may be present Liver disease and cirrhosis Lethargy, hypotonia Mental retardation... 

Alcohol intake is the most important cause of liver cirrhosis in the Western world [2]. Data from the World Health Organization show that the incidence of chronic liver disease and cirrhosis associated with alcohol in the UK is 10.42 per 100 000 people [3]. Interestingly, only around... 

Arkenan, H.-T., Stichtenoth, D.O., FrohRch, J.C., Manns, M.P., Bdker, K.-H.W. Elevated nitric oxide levels in patients with chronic liver disease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation. Z. Gastroenterol. 2002 40 907—912... 

Muhow, C., V. Lawrence, B. Jacobs, et al. 2000. MUk thistle Effects on liver disease and cirrhosis and clinical adverse effects. Evid Rep. Technol. Assess. (Summ.) 21 1-3. 

Worldwide, 15 million HBsAg carriers are also infected with hepatitis D/delta virus (HDV) (Gaeta et al. 2000). This situation represents a major therapentic challenge, as most of these patients have advanced liver disease, inclnding cirrhosis in 60-70% of cases, and hepatocellular carcinoma (Fattovich et al. 2000 Saracco et al. 1987). No specific HDV inhibitors have been developed, and IFN-a-based treatment is more difficnlt in HBV-HDV infection than in HBV monoinfection. HDV RNA levels in sernm can be nsed to monitor treatment efficacy. The endpoint of therapy is HDV RNA clearance and ALT normalization, and this is sometimes achieved after the end of treatment. A snstained response can lead to HBsAg clearance from serum. 

The incidence of liver complications associated with PN ranges from approximately 7% to 84%, and end-stage liver disease develops in as many as 15% to 40% of adult patients on long-term PN.35 Patients often develop a mild increase in liver enzymes within 1 to 2 weeks of initiating PN, but this generally resolves when PN is discontinued. Severe liver complications include hepatic steatosis (fat deposition in liver), steatohepatitis (a severe form of liver disease characterized by hepatic inflammation that may progress rapidly to liver fibrosis and cirrhosis), cholestasis, and cholelithiasis.35... 

Steatohepatitis A severe form of liver disease caused by fat deposition in the liver, characterized by hepatic inflammation that may rapidly progress to liver fibrosis and cirrhosis. 

Type A HE is induced by acute liver failure, Type B results from portal-systemic bypass without intrinsic liver disease, and Type C occurs with cirrhosis. HE may be classified as episodic, persistent, or minimal. 

The main indications for liver transplantation include chronic hepatitis C, alcoholic liver disease, nonalcoholic fatty liver disease, and cryptogenic cirrhosis. 

Hypokalemia - Hypokalemia may develop during concomitant corticosteroids, ACTH, and especially with brisk diuresis, with severe liver disease or cirrhosis, vomiting or diarrhea, or after prolonged therapy. 

Chronic HCV- In combination with peginterferon alfa-2a for the treatment of adults with chronic HCV infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A). 

Adverse effects include anorexia, nausea, vomiting, diarrhoea and/or constipation, weight gain, skin rash hair loss, neutropenia, tremors and ataxia are occasionally reported. Valproic acid is contraindicated in liver disease, especially cirrhosis, pregnancy and hypersensitivity. 

Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. Milk thistle has most often been studied in the treatment of alcoholic hepatitis and cirrhosis. In both of these disorders, outcomes have been mixed and reports include significant reductions in markers of liver dysfunction and in mortality, as well as no effect. In acute viral hepatitis, studies have generally involved small sample sizes and have shown mixed outcomes of improved liver function (eg, aminotransferase values, bilirubin, prothrombin time) or no effect. Studies in chronic viral hepatitis and toxin-induced injury have also been of small size but have reported mostly favorable results. Parenteral silybin is marketed and used in Europe as an antidote in Amanitaphalloides mushroom poisoning, based on favorable outcomes reported in case-control studies. 

T. Sawamura, H. Nakada, H. Hazama, Y. Shiozaki, Y. Sameshima, and Y. Tashiro, Hyperasialoglycoproteinemia in patients with chronic liver diseases and/or liver cell carcinoma. Asialoglycoprotein receptor in cirrhosis and liver cell carcinoma, Gastroenterology 87 1217-1221 (1984). 

Causes of cirrhosis can usually be identified by the patient s history combined with serological and histological investigation. Alcoholic liver disease and hepatitis C and B are the most common causes of cirrhosis. The association of excessive alcohol consumption with liver disease has been recognised for centuries. After the identification of the hepatitis C vims and of non-alcoholic steatohepatitis in obese patients with diabetes, the diagnosis of cirrhosis without an apparent cause (cryptogenic cirrhosis) is rarely made. Genetic causes of cirrhosis include haemochromatosis and Wilson s disease. 

Systemic vasodilatation, the severity of liver disease and portal pressure contribute to the abnormalities of sodium handling in cirrhosis. 

Drug metabolism is impaired in patients with liver disease, with CYP-mediated reactions affected more than phase 2 enzymes [35]. Impairment of CYP expression and activity correlates with the severity of liver disease and also, for some of the enzymes, the aetiology of cirrhosis. 

The principle of Paracelsus is crucial here, and the emphasis must be on the word moderate , as there is no doubt that higher levels of drinking lead to liver disease and a variety of other diseases. It is no accident that the level of liver cirrhosis is also relatively high in France. 

Diuretics are highly efficient drugs for the treatment of edema associated with congestive heart failure. They are also used to increase the volume of urine excreted by the kidneys [9]. For example, duranide, 81, a dichlorinated benzene disulfonamide, is an oral carbonic anhydrase inhibitor. Duranide reduces intraocular pressure by partially suppressing the secretion of aqueous humor [11]. Diuril, 82, has an antihypertensive activity and is issued to control blood pressure [9]. Edecrin, 83, is an unsaturated ketone derivative of an aryloxyacetic acid. Edecrin is used in the treatment of the edema associated with congestive heart failure, renal disease, and cirrhosis of the liver [11]. Amiloride, 84, is also used as an adjunctive treatment with thiazide diuretics in congestive heart failure hypertension. 

Absorption of theophylline from the gastrointestinal tract is usually rapid and complete. Some 90% is metabolised by the liver and there is evidence that the process is saturable at therapeutic doses. The tis 8 h, with substantial variation, and it is prolonged in patients with severe cardiopulmonary disease and cirrhosis. Obesity and prematurity are associated with reduced rates of elimination, whereas tobacco smoking enhances theophylline clearance by inducing hepatic P450 enzymes. Because of these pharmacokinetic factors and low therapeutic index, monitoring of the plasma theophylline concentration is necessary to optimise its therapeutic effect and minimise the risk of adverse reactions the optimum concentration range is 10-20 mg/1 (55-110 mmol/1). 

A new nomenclature of HE existing since 2002 distinguishes three forms (7.) type A (= HE associated with acute liver failure), (2.) type B (= HE associated with portosystemic bypass without liver disease), and (2.) type C (= HE associated with liver cirrhosis). 

Portosystemic encephalopathy (PSE) develops in chronic liver diseases and/or in the wake of portosystemic circulation. Liver cirrhosis with its hepatofugal collateral circulatory pathway is thus the focus of interest in this clinical form of disease. The term PSE is identical to exogenous liver coma or liver cell failure coma . PSE can be further subdivided according to its symptomatology and depending on its form and degree of severity. There are three forms of portosystemic encephalopathy (1.) subclinical (or latent) PSE, (2.) acute or acute recurrent (episodic) PSE, and (i.) chronic recurrent or chronic persistent PSE. 

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