Serum concentrations and excretion of bile acids in cirrhosis.

Bile acid concentrations in serum, and urinary and faecal excretion of bile acids have been studied in ten patients with liver cirrhosis as a consequence of alcohol abuse. Eight of the patients were categorized as Child group A, whereas the remaining two patients comprised Child group C. Individual bile acids were isolated and identified by gas chromatography coupled to mass spectrometry. Total fasting serum bile acid concentrations were elevated in all patients, but not correlated to conventional tests of liver function. Eight of the patients had increased urinary excretion of bile acids. Faecal bile acid-excretion was highly variable between patients, and also between Child's group A and C patients. Total fasting serum bile acid concentrations were not correlated to either urinary, faecal, or total bile acid excretion (= synthesis of bile acids) or to the ratio between urinary and faecal excretion of bile acids. The daily synthesis of bile acids showed a large overlap between Child's group A and C patients. The percentage of chenodeoxycholic acid and its metabolites relative to total daily excretion of bile acids did not correlate, indicating that the synthesis pathways for the primary bile acids does not systematically change in relation to the rate of synthesis. We conclude that even in mild cirrhosis, serum bile acid concentrations are elevated. However, no consistent changes in synthesis of bile acids or synthesis pathways was observed in such patients.     

Serum bile acids in alcoholic liver disease. Comparison with histological features of the disease.

Fasting serum bile acids were measured by gas-liquid chromatography in 64 patients with alcoholic liver disease and compared with histological features in their percutaneous liver biopsy specimens. Total bile acid concentrations were normal (less than 2 mug/ml) or minimally increased in 6 patients in whom fatty infiltration was the only hepatic lesion. In the remaining 58 patients with more severe histological lesions, levels were increased in 93%, whereas serum bilirubins were elevated in only 43%. Chenodeoxycholic acid was usually the predominant serum bile acid, regardless of the degree of necrosis or connective tissue change in the biopsy specimen. Only small amounts of the secondary bile acids, deoxycholic acid and lithocholic acid, were detected. Levels of these secondary bile acids did not correlate with histological features.     

Serum levels of magnesium in hepatic cirrhosis

In a group of 50 patients with liver cirrhosis compared with a group of 50 clinically healthy subjects serum magnesium levels were determined. The patients were divided according the aetiology of liver cirrhosis and to the presence or not of ascite and cholestasis. The serum magnesium levels were related to the main laboratory tests used in liver cirrhosis. The patients present a significant decrease of serum magnesium levels in comparison to controls. The patients with alcoholic cirrhosis of the liver and with ascite have significant lower magnesium levels in comparison with the patients with post-hepatitis cirrhosis and with patients without ascite. There is a significant correlation between serum magnesium levels and serum levels of aldosterone, albumin, gamma-glutamyl transpeptidase and total pool of bile acids. Direct and indirect effects of alcohol, a secondary hyperaldosteronism, the use of diuretics, and hypoalbuminaemia could account for magnesium serum level decrease in liver cirrhosis.     

Transport of serum bile acids in patients with liver cirrhosis and hyperbilirubinaemia

From 12 patients with liver cirrhosis and hyperbilirubinaemia, the different conjugates of bilirubin and bile acids in the serum were separated and determined. The serum of the patients contained varying amounts of unconjugated bilirubin, which was not correlated to total serum bilirubin. No correlation between bilirubin conjugates and different conjugates of bile acids could be found, indicating different elimination processes for these substances. To examine whether a changed plasma transport of bile acids, which may contribute to the different excretion pattern of bilirubin and bile acids, occurs in liver cirrhosis, the bile acids in the different serum lipoprotein fractions were determined in seven of the patients. It was found that 40% of serum bile acids were bound to serum lipoproteins, despite decreased serum lipoprotein levels. The degree of lipoprotein binding of bile acids was not correlated to total serum bile acid concentrations. Cholic acid conjugates were present to a higher extent in the lipoprotein fractions than those of chenodeoxycholic acid or of deoxycholic acid. Determination was made of the distribution of individual conjugates between different lipoproteins and it was found that most of the glycine conjugates were present in high density lipoprotein, whereas the main part of sulphates and taurine conjugates were present in low density lipoprotein. These results indicate that a higher fraction of bile acids in liver cirrhosis is transported by lipoproteins in plasma, which may be of importance for the hepatic elimination of bile acids in cases with this disease.     

Red blood cell status in alcoholic and non-alcoholic liver disease.

Macrocytosis is most commonly associated with vitamin B(12) and folic acid deficiency, followed by alcoholism, liver disease, and other pathologic conditions. We studied the red cell and vitamin status in 423 consecutive patients with various liver diseases, including 31 with acute viral hepatitis (AVH), 105 with chronic hepatitis (CH), and 134 with alcoholic liver disease (ALD), who consisted of 84 with non-cirrhotic alcoholic liver disease (NCALD) and 50 with alcoholic liver cirrhosis (ALC), 60 with non-alcoholic liver cirrhosis (NALC), and 93 with hepatocellular carcinoma (HCC). The mean corpuscular volume (MCV) and red cell distribution width (RDW) were significantly higher in patients with ALD and NALC, and among them macrocytosis occurred more frequently in patients with ALC. Macrocytic anemia was mostly found in cirrhotic patients, in which the Child-Pugh score was closely related to the development of macrocytic anemia. In ALD, the MCV was significantly correlated with the estimated alcohol consumption and inversely correlated with the serum folic acid level, which, however, was often maintained within the normal range in patients with macrocytic ALC. After abstinence from alcohol, the MCV and RDW were reduced significantly and were associated with an increasing serum folic acid level. This suggests that macrocytic anemia was a common feature of alcoholic and non-alcoholic liver cirrhosis and that alcohol abuse and folic acid deficiency play a secondary role in macrocytosis.     

Serum proteins in liver cirrhosis: effects of shunt surgery

The serum protein patterns of 38 patients with alcoholic liver cirrhosis were studied and compared with those of 15 patients with cryptogenic cirrhosis and of 18 normal volunteers. Serum prealbumin and albumin were significantly lowered in alcoholic liver cirrhosis in comparison with the normals. In liver cirrhosis, the four acute phase reactants, alpha 1-antiproteinase, orosomucoid, and haptoglobin and caeruloplasmin, showed a pattern in serum, in which alpha 1-antiproteinase was increased, orosomucoid and haptoglobin were decreased, and caeruloplasmin was normal. Immunoglobulins G, A and M were significantly elevated. IgA was significantly more elevated in patients with alcoholic disease than in patients with cryptogenic cirrhosis. The construction of a surgical portal-systemic shunt resulted in a significant decrease in serum concentrations of the acute phase reactants, while prealbumin, albumin and immunoglobulins were unaffected.     

Bile constituents in ascitic fluid

Bile acids and other bile constituents were determined in serum and ascites from eight patients with liver cirrhosis and in ascites secondary to malignancy in six patients. In cirrhotic ascites, total bile acid levels averaged 53% of the serum levels. A positive correlation was evident between ascites and serum levels for both cholic and chenodeoxycholic acid. For cholic acid, the ascites to serum ratio was higher in all patients compared with the corresponding ratio for chenodeoxycholic acid. The ascites to serum ratios for glycine, taurine and sulphate conjugates were similar, no tendency being shown by any of the conjugates to leak more easily into ascites. The high levels of bile acids in cirrhotic ascites suggests that the abdominal cavity harbours a fraction of the bile acid pool, which should be taken into account when studying bile acid turnover in liver cirrhosis. Bilirubin levels in cirrhotic ascites averaged 24% of the serum values. A positive correlation between ascites and serum levels for unconjugated bilirubin was recorded, whereas the occurrence of bilirubin conjugates in ascites was variable. Albumin levels in cirrhotic ascites were 25% of the serum levels. The ascites to serum ratios for other proteins such as IgG, IgA and IgM and also cholesterol and phospholipids were lower than that for albumin. In malignant ascites, a pattern different from that in liver cirrhosis was seen, low bile acid levels being found. No difference between bilirubin levels was observed, while albumin and cholesterol levels were higher in malignant ascites, with no overlap between the patient groups. These results indicate that the complex mechanisms of ascites formation result in variable levels of bile constituents in ascitic fluid, which are further dependent on the underlying disease.     

gamma-Glutamyl transpeptidase activity in liver disease: serum elevation is independent of hepatic GGTP activity

gamma-Glutamyl transpeptidase activity was measured in liver and serum from 110 patients undergoing diagnostic liver biopsy, including patients with alcoholic liver disease, fatty liver not due to alcohol, primary biliary cirrhosis, persistent hepatic disease, chronic active hepatitis and normal livers. Serum gamma-glutamyl transpeptidase was markedly elevated in patients with alcoholic liver disease and primary biliary cirrhosis while mean hepatic gamma-glutamyl transpeptidase activity was significantly increased only in the alcoholic liver disease group. There was considerable overlap of individual enzyme values among the different disease groups. There was no inhibitors or activators of liver gamma-glutamyl transpeptidase in any of these disorders. The increased liver activity was not related to the degree of hepatic fibrosis or cirrhosis. There was no correlation between hepatic and serum gamma-glutamyl transpeptidase activity. Hepatic and serum gamma activities were equally increased in individuals with alcoholic liver disease whether or not they were drinking at the time of the study. The data suggest that increased hepatic gamma-glutamyl transpeptidase activity is neither specific for alcoholic liver disease nor essential for serum GGTP to be elevated.     

Presence of bile acid metabolites in serum, urine, and faeces in cirrhosis.

Studies have been made of the presence of bile acid metabolites in ten patients with liver cirrhosis as a consequence of alcohol abuse. Eight of the patients were categorized as Child group A, indicating only mild impairment of liver function, whereas the remaining two patients comprised Child group C. A complex mixture of bile acids was isolated from serum, urine, and faeces, and 26 bile acids were identified by gas-liquid chromatography coupled to mass spectrometry. Identification was made of the primary bile acids, cholic (C) and chenodeoxycholic (CDC) acid, and metabolites of these bile acids converted through 7-dehydroxylation, keto-formation, 6-hydroxylation, 1 beta-hydroxylation, allo-formation or nor-formation. All of the bile acids have previously been described either in healthy humans or patients with hepatobiliary disease. With the exception of C, CDC, and deoxycholic acid, all of the bile acids were present only infrequently, and none of the bile acids was pathognomonic for liver cirrhosis. The proportion of metabolites of the primary bile acids C and CDC was similar to that previously reported in healthy humans, the lowest proportion being recorded in the Child group C patients. Repeated determinations of the metabolite pattern in two patients showed large variations, indicating that the bile acid metabolism varies from time to time. We conclude that in mild cirrhosis, no significant alterations in microbial or hepatic transformation of bile acids seem to occur.     

血清总胆汁酸测定在肝胆疾病诊断中的应用

目的探讨胆汁酸（TBA）在诊断肝胆疾病中的临床价值。方法采用循环酶速率法检测了140例病人,其中37例急性肝炎患者,45例慢性肝炎患者,20例肝硬化患者,25例肝癌患者,13例胆管阻塞患者。并与62例健康对照组的血清总胆汁酸含量进行比较。结果各类肝胆疾病患者TBA均显著高于健康对照组（P〈0.01）,其中TBA的阳性率在急性肝炎组、肝硬化组及肝癌组均〉80%。结论TBA检测简便实用,对肝胆疾病的临床诊断有重要的临床意义。     

Diagnostic significance of determining the blood content of lactic and uric acids in chronic liver lesions of alcoholic and viral etiologies

The concentration of lactic and uric acids in blood serum was measured in 115 patients with chronic liver lesions of virus (30 patients) and alcoholic (85 patients) etiology. The highest rise of lactic and uric acid concentrations was recorded in patients with alcoholic hepatitis and active alcoholic liver cirrhosis. The blood concentration of lactic and uric acids in alcoholic hepatopathy increased in parallel with an increment of the gravity of the pathological process, being the highest in patients with alcoholic hepatitis (lactic acid) and liver cirrhosis associated with the edematous ascites syndrome (uric acid). In inactive liver cirrhosis of alcoholic etiology, the concentrations of lactic and uric acids tended toward reduction, however, they were significantly higher than in the group of patients with virus liver lesions. Normal or negligible rises in the content of lactic and uric acids were seen in the groups of patients with chronic liver diseases of virus etiology. It is concluded that the measurement of the content of lactic and uric acids plays a diagnostic part in different patterns of alcoholic hepatopathies.     

1-14C]Ethanol breath test in alcoholic liver disease

The activity of ethanol metabolising enzymes was assessed in 51 patients with alcoholic and non-alcoholic liver disease using tracer doses of [1-14C]ethanol and measuring 14CO2 excretion in the breath. Alcoholic patients with only fatty infiltration of the liver showed significantly increased activity compared with controls. Comparing alcoholic patients with cirrhosis and a serum albumin greater than 28 g/l, activity in those with a recent history of continued heavy drinking was significantly greater than in patients who had abstained from alcohol. In addition, both groups of alcoholic cirrhosis showed significantly more activity than patients with non-alcoholic cirrhosis. The activities of patients with acute alcoholic or viral hepatitis were normal when their prothrombin times were less than 7 sec prolonged, but were reduced when prolongation exceeded 7 sec. These results demonstrate that in chronic alcoholic liver disease, even with cirrhosis, alcohol can still increase the activity of ethanol oxidising enzymes provided hepatic function remains adequate. However, this response is lost in acute liver damage and in chronic alcoholic disease with severe hepatic dysfunction.     

血浆同型半胱氨酸水平与酒精性肝硬化关系的初步探讨

目的:观察血浆同型半胱氨酸(Hcy)水平对酒精性肝硬化的影响。方法:选择酒精性肝硬化12例、肝炎后肝硬化51例、混合性肝硬化21例及健康人群40例,测定血浆Hcy、叶酸、维生素B12(VitB12)、丙氨酸氨基转移酶(ALT)、γ-谷氨酰转肽酶(GGT)、碱性磷酸酶(ALP)、总胆红素(T-Bil)、总胆汁酸(TBA)、白蛋白(Alb)的水平。结果:酒精性肝硬化患者血浆同型半胱氨酸水平明显升高(P<0.01),酒精性肝硬化患者较肝炎后肝硬化患者明显升高(P<0.05);同型半胱氨酸水平与酒精性肝硬化患者Child-Pugh得分呈负相关(r=-0.602,P<0.05)。结论:肝硬化患者血浆Hcy水平较正常人是升高的,且其在酒精性肝硬化患者升高更为显著。酒精性肝硬化患者随着肝脏损伤程度的逐渐增加,血浆Hcy水平是降低的。     

Serum chemistry templates of disease in liver, pancreas, and gallbladder.

On routine hospital admission, 23,714 patients received a 28-test serum metabolic profile. The 33 most common diseases (4,132 patients) of liver, pancreas, and gallbladder (LPG) had unique chemical templates averaging 15 significant serum deviations. Each LPG disease differed from all others by elevations of both leucine-aminopeptidase (LAP) and alkaline phosphatase (AP) levels. LAP level was low or normal and serum glutamic oxaloacetic transaminase (SGOT) and AP levels were elevated in 43 non-LPG diseases. Patients with acute and chronic pancreatitis had elevated amylase levels. The four nonmalignant diseases of the gallbladder were associated with normal levels of amylase and lactic dehydrogenase (LDH); except for silent cholelithiasis, each showed elevated total bilirubin (BIL) levels. Patients with solitary or scattered lesions of the liver had normal bilirubin levels (2,115 patients), and those with diffuse interstitial or parencymal disease had elevated BIL levels. Cancer patients had elevated LDH and alpha1 globulin (A1G) levels, but low albumin levels. The importance of comprehensive liver profiles in the treatment of psychoses is emphasized by significant liver damage in a number of these patients. A1G was normal and LDH was elevated in patients having mononucleosis, hepatitis, lupus erythematosus, alcoholism, and alcoholic cirrhosis.     

Inhibition of serum alkaline phosphatase activity by phenylalanine and cholic acid.

Serum alkaline phosphatase activity was found to increase more markedly in patients with liver cirrhosis than in patients with peptic ulcer and this increase was found to be influenced by blood types. After testing several amino acids and bile acids, phenylalanine and cholic acid were chosen and their inhibitory effects upon serum alkaline phosphatase activity were studied in 66 patients with various liver diseases. It was found that the combination of both agents demonstrates different patterns of inhibition between the patients with liver cirrhosis and obstructive jaundice. This inhibitory effects were also variable among cases of different blood types. Basing upon the present observation, the possible source of the elevated alkaline phosphatase activity in liver cirrhosis was discussed.     

Serum unconjugated bile acids in patients with small bowel bacterial overgrowth

Concentrations of total and unconjugated bile acids in serum were measured fasting and 2 h postprandially in 9 patients with a positive [14C]glycocholate breath test consistent with small bowel bacterial overgrowth and in 13 controls. Gas-liquid chromatography-mass spectrometry (GLC-MS) and enzymatic-fluorometric assays were both used. In contrast to previous work, total serum bile acids were only occasionally elevated in patients with bacterial overgrowth. Total 2 h postprandial unconjugated bile acids, however, were elevated in 7/9 patients when measured by GLC-MS and in 6/9 when measured by the enzymatic-fluorometric method. The best separation between patients and controls was achieved by GLC-MS determinations of 2 h postprandial unconjugated cholic acid or primary bile acids, which were abnormal in 8/9 patients. This study indicates that measurement of serum bile acids may be a useful approach to the diagnosis of bacterial overgrowth, but would require accessible methods for separating and measuring cholic acid or unconjugated primary bile acids in post-prandial sera.     

Clinical evaluation of serum levels of tryptophan in hepatobiliary disease

Fasting serum levels of total and free tryptophan, and free fatty acids and albumin, were measured and compared by blood biochemical analysis in patients with hepatobiliary disease and neuropsychiatric symptoms. The serum total tryptophan level tended to be elevated in patients with chronic active hepatitis, hepatic coma and obstructive jaundice, but not significantly. The serum free tryptophan level was significantly elevated in patients with chronic active hepatitis, liver cirrhosis, primary hepatocellular carcinoma and obstructive jaundice. The free tryptophan level was related to the decreased serum albumin level and elevated serum free fatty acid levels, which seems to indicate a connection with liver parenchymal function. The level, however, seemed not to correlate with neuropsychiatric symptoms.     

Erythrocyte membrane lipids and serum selenium in post-viral and alcoholic cirrhosis

Erythrocyte-membrane fatty acid composition and cholesterol content were evaluated along with serum selenium in 33 patients with liver cirrhosis and in 40 normal subjects. Thirteen patients were suffering from post-viral (group V) and 20 from alcoholic (group A) cirrhosis. The aim of the study was to elucidate whether membrane lipid abnormalities in cirrhosis were linked to the aetiology of the disease or whether they were the results of the cirrhotic process itself. The patients presented a significant increase in membrane cholesterol, palmitic acid (C16:0) and saturated fatty acids (SFA), and a decrease in polyunsaturated fatty acids (PUFA) and polyunsaturated/saturated fatty acids ratio (P/S) compared with the control group. Serum selenium levels were significantly reduced. When patients were subdivided according to aetiology, the alcoholic patients showed greater lipid composition abnormalities than the viral cirrhotics (higher levels of SFA and lower PUFA and P/S), while pathologic palmitic acid, membrane cholesterol and serum selenium values were confirmed in both groups of patients.

In conclusion, low serum selenium and a series of erythrocyte membrane lipid composition abnormalities would appear to be features peculiar to cirrhosis. Alcoholic cirrhotics, on the other hand, show a more deranged erythrocyte membrane lipid profile.     

Bile-acid metabolism and the liver.

Primary bile acids are exclusively synthesize, and all bile acids are conjugated, in the liver. When hepatic function is altered by disease, not surprisingly the bile-acid metabolism reflects this change. 1. In chronic liver disorders the glycine: taurine ratio of serum and bile is reduced. 2. In cases of relapsing acute hepatitis and relapsing chronic active hepatitis the serum bile acids are increased, providing an aid to early diagnosis. Their pattern often distinguishes chronic cholestatic conditions from Laennec's cirrhosis. 3. In chronic liver disease, the concentration of intraduodenal bile acids is reduced; when the reduction is severe, this probably accounts for co-existent steatorrhoea. 4. In Laennec's cirrhosis, both the synthesis and pool size of cholic acid are markedly depressed; in primary biliary cirrhosis, however, preliminary data indicate a decrease in the chenodeoxycholic acid component.     

A common polymorphism in the ABCB11 gene is associated with advanced fibrosis in hepatitis C but not in non-alcoholic fatty liver disease

Chronic HCV (hepatitis C virus)-associated cirrhosis represents a major indication for liver transplantation. Bile acids contribute to hepatic stellate cell activation as a key event in fibrogenesis. The aim of the present study was to investigate the role of bile acids and polymorphisms in bile acid level-regulating genes on fibrosis progression. A total of 206 subjects with chronic HCV infection were included for ABCB11 (ATP-binding cassette, subfamily B, member II) 1331T>C and NR1H4 (nuclear receptor) -1G>T genotyping, 178 of which were analysed for fibrosis stage. Exclusion criteria were HBV (hepatitis B virus) or HIV coinfection, alcohol >40 g/day and morbid obesity. A total of 358 patients with NAFLD (non-alcoholic fatty liver disease) were genotyped for comparison with a non-viral liver disease. Caucasian individuals (n = 110), undergoing liver resection for focal hepatic metastasis, served as controls. The ABCB11 1331C allele was significantly overrepresented in HCV patients compared with controls {allelic frequency 62.9%; OR (odds ratio), 1.41 [95% CI (confidence interval), 1.012-1.965]}. Median plasma bile acid levels were not significantly increased in the CC compared with TT genotype [7.2 (1-110) μmol/l compared with 3.5 (1-61) μmol/l; values are medians (range). A significant association between the presence of cirrhosis and ABCB11 genotype (CC compared with CT or TT, P=0.047) was observed in the χ2 test and independent of other risk factors of age, gender, body mass index and disease duration in multivariate analysis (P = 0.010). No such association could be observed in fatty liver patients with regard to advanced fibrosis (F ≥ 2). The common ABCB11 1331CC genotype, which is present in 40% of HCV patients and renders the carrier susceptible to increased bile acid levels, is associated with cirrhosis.