Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amifostine is a broad-spectrum cytoprotective agent approved for protection against cisplatin toxicities and radiation-induced xerostomia; strong clinical evidence exists that amifostine protects normal mucosa and lung from radiation damage. Hypotension, nausea/vomiting, fatigue and fever/rash are the main side-effects associated with amifostine administration. The present study summarizes our experience on daily amifostine administration to cancer patients with various coexisting medical conditions and diseases. The tolerance and the eventual interference of amifostine with the course of the coexisting diseases is reported, providing a core list of medical conditions met in radiotherapy practice, their compatibility with amifostine administration and recommendations on how to deal with these patients. This list comprises genetic diseases (xeroderma pigmentosum, glucose-6-phosphate dehydrogenase deficiency), autoimmune disorders (vitiligo, scleroderma, thyroiditis, perforating collagenosis), metabolic diseases (diabetes mellitus), cardiovascular diseases, neuro/psychiatric diseases and other medical conditions (hypoglycemia, hepatic cirrhosis, alcoholism). A high incidence of fever/rash was noted in patients with autoimmune diseases, while all other conditions did not alter the patterns of side-effects expected following amifostine administration.
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PMID:Amifostine administration during radiotherapy for cancer patients with genetic, autoimmune, metabolic and other diseases. 1642 30

Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type Ia involves the liver, kidney and intestine (and Ib also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type IIIa involves both the liver and muscle, and IIIb solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type VI and IX are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type XI is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type II is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and VII involve only the muscle.
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PMID:Glycogen storage diseases: new perspectives. 1755 1

A review of 118 cases of histologically diagnosed hepatocellular carcinoma in Riyadh Central Hospital over a 15-year period from 1985 to 1989, showed that there were 73 Saudi nationals and 45 other nationalities. The overall sex ratio was 2.5;1, M:F (1.92:1 in Saudis; and 4:1 in other nationalities). The mean age for male Saudis was 61.2 years (range, 34-85) and for females 60.9 years (range, 18-80). Peak incidence occurred at 50 years for males and 60 years for females. Hemoperitoneum from ruptured tumor (7 cases) and 1 case of recurrent hypoglycemia were noted in the series. Tumor grading was Grade I, 10 (11.5%); Grade II, 49 (56.3%); Grade III, 28 (32.2%). Cirrhosis was associated with tumor in 58.0% of cases. Hepatitis B surface antigen was positive in 47.5% of Saudis and 47% in the whole group. Schistosomal serology was available in 21 cases and positive in 85.7%. The importance of hepatitis B virus in etiopathogenesis of hepatocellular carcinoma is reflected in this study.
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PMID:Hepatocellular carcinoma: A clinicopathological analysis of 118 cases from Riyadh Central Hospital. 1758 35

Mitochondrial dysfunction is a major mechanism whereby drugs can induce liver injury and other serious side effects such as lactic acidosis and rhabdomyolysis in some patients. By severely altering mitochondrial function in the liver, drugs can induce microvesicular steatosis, a potentially severe lesion that can be associated with profound hypoglycaemia and encephalopathy. They can also trigger hepatic necrosis and/or apoptosis, causing cytolytic hepatitis, which can evolve into liver failure. Milder mitochondrial dysfunction, sometimes combined with an inhibition of triglyceride egress from the liver, can induce macrovacuolar steatosis, a benign lesion in the short term. However, in the long term this lesion can evolve in some individuals towards steatohepatitis, which itself can progress to extensive fibrosis and cirrhosis. As liver injury caused by mitochondrial dysfunction can induce the premature end of clinical trials, or drug withdrawal after marketing, it should be detected during the preclinical safety studies. Several in vitro and in vivo investigations can be performed to determine if newly developed drugs disturb mitochondrial fatty acid oxidation (FAO) and the oxidative phosphorylation (OXPHOS) process, deplete hepatic mitochondrial DNA (mtDNA), or trigger the opening of the mitochondrial permeability transition (MPT) pore. As drugs can be deleterious for hepatic mitochondria in some individuals but not in others, it may also be important to use novel animal models with underlying mitochondrial and/or metabolic abnormalities. This could help us to better predict idiosyncratic liver injury caused by drug-induced mitochondrial dysfunction.
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PMID:Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. 1870 45

Relationship between cirrhosis and renal dysfunction is not yet fully understood. A model of cirrhosis with acute hepatic and renal damage (RF), produced by CCl4 in rats, with hemodynamic and renal functional alterations, similar to those observed in decompensated cirrhosis (DC) in man, was used to study chemical nephrotoxicity in animals. We performed in male Wistar rats hepatic and renal functional and hemodynamic studies in control, cirrhotic and decompensated cirrhotic (DC) groups. Cirrhosis was induced with carbon tetrachloride by chronic administration. Association between liver and renal functional alterations was detected in rats with decompensated cirrhosis, showing fall in mean arterial pressure and reduction of glomerular filtration rate and filtration fraction. Renal hemodynamics did not change in cirrhotic rats, similarly to what occurs in compensated cirrhotic patients. However, DC rats exhibited increased sodium, glucose and phosphate urinary excretions and decreased ATP in renal cortex. DC animals had severe hypoglycemia. There was an extensive liver fibrosis. Glomeruli had hypercellularity and tubules showed extensive vacuolization in cirrhotic and DC rats. The present study suggests that in this model, damage typical of acute tubular necrosis ensues in cirrhotic rats. We describe functional and morphological damage in liver and kidney in a model of cirrhosis that might predispose to the development of acute renal failure when an individual with hepatic damage is exposed in acute way to chemical toxicants.
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PMID:Acute renal failure induced by carbon tetrachloride in rats with hepatic cirrhosis. 1903 32

Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies.
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PMID:Mitochondrial involvement in drug-induced liver injury. 2002 Feb 67

Uip to 20% of patients with liver cirrhosis develop hepatogenous diabetesdue to the hepatocellular functional loss and insulin resistance. Optimizing diabetic metabolic conditions is not only important to avoid typical late complications of diabetes, but also cirrhosis-associated complications e.g. gastrointestinal bleeding, hepatic encephalopathy or the occurence of hepatocellular carcinoma. So far there have beenno recommendations orguidelines for the diagnosis and treatmentof hepatogenous diabetes. The medical teatment of a diabetic condition is mainly influenced by its side effects. The risk of hypoglycemia must be considered carefully during drug treatment, especially in patients with chronic alcohol abuse. Suitable oral antidiabetics are glinides and short-acting sulfonylureas or possibly meal-related insulin administration with short-acting insulins or rapid-acting insulin analogues. Biguanide and PPAR-gamma agonists are contraindicated because of side effects in liver cirrhosis. Regarding basic treatment, an adequate daily energy and protein supply should be ensuredbecause the majority of patients with liver cirrhosis are malnourished.
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PMID:[Metabolic disturbances in liver cirrhosis (part 2), hepatogenous diabetes: diagnostic aspects and treatment]. 2035 3

Early stage hepatocellular carcinoma is a symptom-free disease. Local and general symptoms occur due to the growth of the tumor tissue and the infiltration of the surrounding blood vessels. Illness progression is indicated by the development of abdominal discomfort, cachexia, therapy-resistant decompensation of previously compensated cirrhosis and in severe cases, the thrombosis of the portal vein or the hepatic veins. Characteristic laboratory findings are the quickly deteriorating blood and liver function tests results, the occurrence of haemostatic disorders and occasional hypoglycemia and/or hypercalcemia. To clarify the etiology and to identify high risk patients, we need to differentiate alcohol-, drug- or chemical-induced hepatic disorders, viral hepatitis B, C and Delta, metabolic disorders and non-alcoholic steatohepatitis. In the case of focal hepatic lesions, persistently elevated alfa fetoprotein levels have a high diagnostic value. At levels over 200 ng/ml, the positive predictive value is >90%. Other, less commonly measured biomarkers are the glycosilated alfa fetoprotein-L3 and the vitamin K-deficiency induced des-gamma-carboxy prothrombin. The risk of tumor occurrence is multiple in patients with HbeAg positive chronic hepatitis B if the virus is of genotype C with mutations in the 1762 and 1764 locations of the core promoter region. Abdominal ultrasound and measurement of alfa fetoprotein is recommended every 6 months for high risk individuals, or every 3-4 months over an 18-24 months period for patients with hepatic lesions of <1cm and of unknown malignancy.
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PMID:[Symptoms of hepatocellular carcinoma. Laboratory tests used for its diagnosis and screening]. 2071 15

Glycogen storage diseases (GSD) and inborn errors of galactose and fructose metabolism are the most common representatives of inborn errors of carbohydrate metabolism. In this review the focus is set on the current knowledge about clinical symptoms, diagnosis and treatment. Hepatomegaly and hypoglycaemia are the main findings in liver-affecting GSD like type I, III and IX. Diagnosis is usually made by non invasive investigations, e.g. mutation analysis. In GSD I, a carbohydrate balanced diet with frequent meals and nocturnal continuous tube feeding or addition of uncooked corn starch are the mainstays of treatment to prevent hypoglycaemia. Liver transplantation has been performed in different types of GSD. It should only be considered in high risk patients e.g. with substantial cirrhosis. Many countries have included classical galactosaemia in their newborn screening programs. A lactose-free infant formula can be life-saving in affected neonates whereas a strict fructose-restricted diet is indicated in hereditary fructose intolerance.
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PMID:Inborn errors of carbohydrate metabolism. 2095 63

Deoxyguanosine kinase deficiency (dGK) is a frequent cause of the hepatocerebral form of mitochondrial depletion syndrome (MDS). A group of 28 infants with severe progressive liver failure of unknown cause was recruited for post mortem search for deoxyguanosine kinase (DGUOK) gene mutations. Four affected patients (14% of the studied group), two homozygotes, one compound heterozygote, and one heterozygote, with DGUOK mutation found on only one allele, were identified. Three known pathogenic mutations in the DGUOK gene were detected, c.3G>A (p.Met1Ile), c.494A>T (p.Glu165Val), and c.766_767insGATT (p.Phe256X), and one novel molecular variant of unknown pathogenicity, c.813_814insTTT (p.Asn271_Thr272insPhe). Profound mitochondrial DNA depletion was confirmed in available specimens of the liver (4%, 15%, and 10% of the normal value) and in the muscle (4%, 23%, 45%, and 6%, respectively). The patients were born with low weights for gestational age and they presented adaptation trouble during the first days of life. Subsequently, liver failure developed, leading to death at the ages of 18, 6, 5.5, and 2.25 months, respectively. Mild neurological involvement was observed in all children (hypotonia, psychomotor retardation, and ptosis). Hypoglycemia (hypoketotic) and lactic acidosis were the constant laboratory findings. Elevated transferrin saturation, high ferritin, and alpha-fetoprotein levels resembled, in two cases, a neonatal hemochromatosis. Liver histopathology showed severe hepatic damage ranging from micronodular formation and cirrhosis to the total loss of liver architecture with diffuse fibrosis and neocholangiolar proliferation. Pancreatic islet cell hyperplasia with numerous confluent giant islets was found in both autopsied infants. Analysis of the natural history of the disease in our patients and the literature data led us to the following observations: (i) islet cell hyperplasia (and hyperinsulinism) may contribute to MDS-associated hypoglycemia; (ii) iron overload may additionally damage mtDNA-depleted tissues; (iii) low birth weight, adaptation trouble, and abnormal amino acids in newborn screening are frequent in dGK-deficient neonates.
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PMID:Post mortem identification of deoxyguanosine kinase (DGUOK) gene mutations combined with impaired glucose homeostasis and iron overload features in four infants with severe progressive liver failure. 2110 80


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