Indicators of inflammation and cellular damage in chronic asymptomatic or oligosymptomatic alcoholics: correlation with alteration of bilirubin and hepatic and pancreatic enzymes

Indicadores bioquímicos e hematimétricos de inflamação e lesão celular em alcoolistas

INDICATORS OF INFLAMMATION AND CELLULAR DAMAGE IN CHRONIC ASYMPTOMATIC OR OLIGOSYMPTOMATIC ALCOHOLICS: CORRELATION WITH ALTERATION OF BILIRUBIN AND HEPATIC AND PANCREATIC ENZYMES

Paulo Borini and Romeu Cardoso Guimarães

RHCFAP/2962

BORINI, P. et al. - Indicators of inflammation and cellular damage in chronic asymptomatic or oligosymptomatic alcoholics: correlation with alteration of bilirubin and hepatic and pancreatic enzymes. Rev. Hosp. Clín. Fac. Med. S. Paulo. 54 (2): 53 - 60, 1999.

SUMMARY: Biochemical and hematimetric indicators of inflammation and cell damage were correlated with bilirubin and hepatic and pancreatic enzymes in 30 chronic male alcoholics admitted into psychiatric hospital for detoxification and treatment of alcoholism. Aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase, alkaline phosphatase, and total bilirubin were altered, respectively, in 90%, 63%, 87%, 23% and 23% of the cases. None of the indicators of inflammation (lactic dehydrogenase, altered in 16% of the cases; alpha-1 globulin, 24%; alpha-2 globulin, 88%; leucocyte counts, 28%) was correlated with alterations of bilirubin or liver enzymes. Lactic dehydrogenase was poorly sensitive for detection of hepatocytic or muscular damage. Alterations of alpha-globulins seemed to have been due more to alcohol metabolism-induced increase of lipoproteins than to inflammation. Among indicators of cell damage, serum iron, increased in 40% of the cases, seemed to be related to liver damage while creatine phosphokinase, increased in 84% of the cases, related to muscle damage. Hyperamylasemia was found in 20% of the cases and significantly correlated with levels of bilirubin, alkaline phosphatase and gamma-glutamyltransferase.

It was indicated that injuries of liver, pancreas, salivary glands, and muscle occurred in asymptomatic or oligosymptomatic chronic alcoholics.

DESCRIPTORS: Alcoholism. Liver. Inflammation. Cell damage. Enzymes.

Abusive chronic alcohol intake causes degenerative, inflammatory, and necrotic damage in various tissues, frequently leading to development of hepatic, pancreatic, muscular, and neural diseases. Alterations of enzymes and other substances that occur in degenerative, inflammatory, and necrotic processes may reflect damage in more than one organ since they are rarely tissue-specific³⁸. Furthermore, the types of laboratory tests and their success in identifying physiopathologic response to high alcohol intake vary widely.

The majority of studies evaluating the behavior of biochemical indicators of inflammation and cell necrosis relate to patients with exuberant clinical symptoms. Observations are scarce at stages where clinical manifestations are not evident or are very mild.

Structural and functional alterations of these patients have been found most frequently in the liver, which occupies a key position in alcohol metabolism and is the most commonly damaged organ, isolated or in association with others, in alcoholics. Serum alterations of liver enzymes may indicate different processes. Alteration of aspartate aminotransferase may indicate microsomal induction or liver cell damage while that of alanine aminotransferase occurs in liver or muscle cell injury. Alteration of alkaline phosphatase may reflect, at least partially, failure in bile excretion through damage of bile channels or cholestasis secondary to pancreatopathy.

This study evaluates the relationship of levels of plasma components employed to identify occurrence of inflammation and necrosis with those of liver and pancreatic enzymes in asymptomatic and oligosymptomatic alcoholics.

MATERIALS AND METHODS

Thirty male chronic alcoholics admitted into the psychiatric hospital for detoxification were considered asymptomatic or oligosymptomatic at the admittance physical exam and clinical anamnestic-structured interview³. The majority belonged to the low and average subgroups of the middle class, as judged from mean income. Twenty-four (81%) were smokers. None of them had used illicit drugs or any medicine in the 30 days before admission.

After being carefully informed, they consented to undergo, in the first 24 hours, laboratory exams: hematimetric analyses and biochemical plasma determinations of bilirubins (total, TB, and fractions), aminotransferases (AT; aspartate aminotransferase, AST, and alanine aminotransferase, ALT), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), albumin and globulins, fibrinogen, prothrombin activity and time, lactic dehydrogenase (LDH), creatine phosphokinase (CPK), amylase, iron, total capacity of iron binding (TCIB), and transferrin saturation index (TSI).

No tests were done for viral antigens, and parasitologic exams were negative for Schistosoma mansoni eggs.

Comparisons were made by chi-squared or Fisher's one-tailed tests when occurrences were less than 5, and by Student's t-test for quantitative variables⁴¹. Data are shown as average + standard deviation, sometimes with the 95% confidence intervals (CI) listed . Variables were correlated using linear regression, correlation coefficient, and Pearson's significance test²⁹.

RESULTS

Demographic characteristics and pattern of alcoholism of the sample are presented in table 1.

Simple increases in enzyme levels occurred in 27 cases (90%) for AST, 19 cases (63%) for ALT, 26 (87%) for GGT and 7 (23%) for AP, or were much less when a cutoff limit of twice the normal levels was used (Table 2). According to both criteria, a significantly lower prevalence of alterations in ALT and AP was noted, compared to AST and GGT. AP elevation was always followed by that of GGT, while in 19 (64%) cases AP was normal with elevated GGT. The GGT/ALT ratio was, on the average, 6.8 + 6.6, and higher than 5 in 13 (44%) patients.

Mild hyperbilirubinemia due to the non-conjugated fraction was observed in 7 (23%) cases (Table 2). Average plasma TB was significantly higher in individuals with elevated AT. While all patients with elevated TB showed high AST (p < 0.002, CI = 15.1 to 56.9) and ALT (p < 0.03, CI = 1.3 to 20.7), only the prevalence of altered ALT and TB were correlated. Positive significant correlation was observed between levels of AT and TB (r = 0.61, p < 0.001 for AST, r = 0.66, p > 0.0001 for ALT) but not between AT and bilirubin fractions.

Alpha-1 globulin was elevated in 7 (24%) cases and alpha-2 in 26 (88%), with corresponding increases in the average values. Prevalence of alteration of alpha-1 globulin was not correlated to those of hepatic enzymes or TB. Prevalence of alpha-2 globulin alteration was significantly higher in patients with elevated GGT, but correlation was not detected between their values (r = 0.16, p > 0.05). Average values of alpha-globulins were not correlated with those of hepatic enzymes or TB, but alpha-1 globulin was significantly correlated with albumin values (r = 0.46, p < 0.01; Tables 3, 4).

LDH was increased in 5 (16%) patients, but these alteration were not correlated to alterations of liver enzymes or TB. The average LDH level was normal and, in subgroups of noral or altered LDH, liver enzymes or TB did not show significant differences (Table 5).

Leucocytosis occurred in 8 (28%) patients, in almost all cases due to neutrophils. There were no significant differences between prevalence of leucocytosis and alterations of bilirubin, liver enzymes, or amylase.

Serum iron was elevated in 12 (40%) patients, and was correlated with elevated bilirubin (p < 0.004) and ALT (p < 0.006). These patients, compared to those with normal iron levels, had significantly higher average levels of AST (p <0.01, CI = 7.7 to 50.3), ALT (p < 0.05, CI 3.5 to 16.4) and AP (p < 0.001, CI = 18.3 to 41.7; Table 7). TCIB was normal in 22 (73%) patients, low in 7 (23%) and high in 1 (4%), while TSI was normal in 19 (63%) and high in 11 (37%). Average levels of TCIB and TSI were normal. Significant correlation was observed between iron and transferrin levels (r = 0.77, p < 0.0001), but not between these and albumin (r = 0.12, p > 0.05 and r = 0.01, p > 0.05, respectively).

CPK was elevated in 25 (84%) patients, but was not correlated with elevations of liver enzymes or TB. While the average CPK level was high, subgroups of elevated or normal CPK did not show significant differences in the levels of liver enzymes or TB (Table 8). CPK levels did not correlate with those of AST (r = 0.20, p > 0.05) or ALT (r = 0.19, p > 0.05).

Amylase was elevated in 6 (20%) patients, and the presence of hyperamylasemia prevalence was significantly higher in hyperbilirubinemics. Average levels of AP and GGT were significantly higher in hyperamylasemics but only AP and amylase levels were correlated (r = 0.53, p < 0.01). Prevalence of hyperamylasemia among cases with elevated AST was 1 : 4.5 (Table 9). Prevalence of alterations and plasma levels of liver enzymes and amylase were not related to time and daily intake of alcohol.

COMMENTS

Except for the better socioeconomic conditions and lower age of patients in this study, the pattern of alcoholism and general clinical conditions did not differ significantly from those observed in our previous study of patients with the same symptomatic profile and in the same hospital⁴.

In this study, higher prevalence of AT, especially AST, alteration was observed, relative to other studies of asymptomatic or oligosymptomatic alcoholics^5,15,16,19. Increased activities of AT were mild in the great majority of patients, with higher than twice the normal values in only 33% (AST) and 13% (ALT) of the patients.

In chronic alcoholics, ALT alteration is a better indicator of liver damage than AST since expression of ALT is restricted to the liver³⁸, while AST may be altered through induction in the liver or after extra-hepatic complications (myopathy, pancreatopathy, hemolysis) due to alcoholism³³. Observations that patients with hyperbilirubinemia showed average AT levels higher than those with normal bilirubinemia, and further that under those circumstances there was a higher prevalence of ALT alterations than of AST, suggests that in 25% of the cases, alcohol aggression resulted in hepatocyte damage. Prevalence of liver cell aggression fell to 13% when only cases with higher than twice the normal levels of enzymes were considered, according to international consensus².

Prevalence of altered GGT (88%) was higher than was observed in another Brazilian study²⁷. AP was lightly altered in only one-fourth of the cases and, while the average level of the enzyme remained normal, that of GGT was about 4-fold the normal value. The divergent behavior of GGT and AP, also reported by others^36,43, could result from both GGT induction^20,35 and from specific actions at the different sites of production of the enzymes⁴³. GGT may be altered in pancreatitis 0. Consequently, elevation of AP would be, relative to GGT, a better clinical indicator of cholestasis. Correlation between plasmatic activities of GGT and AST could be explained through concerted alcohol induction.

In 80% of cirrhotics, mainly alcoholics, it was observed that the ratio GGT / ALT was > 5 ^{9, 42}. This ratio was reached in 44% of the patients in the present study, which could indicate cirrhosis in 4 or 5 of them.

In alcoholic hepatitis, especially in intense acute forms, increased synthesis and elevation of alpha-globulins has been reported⁴⁰. Otherwise, they were reduced in chronic inflammation with mesenchymal reaction, in parallel with albumin levels³⁸. In the present study, prevalence and degrees of alteration were different for their fractions, low for alpha-1 and high for alpha-2 globulin. The differences could be related to biologic and physico-chemical characteristics of their constituent glycoproteins and lipoproteins as well as to concomitant alterations of other substances. Previous observations³⁸ were consistent with our findings of correlation between alpha-1 globulin and albumin, where low alpha-1 globulin occurred in cases with hypoalbuminemia. The possibility of relating the significant increase of alpha-2 globulin with that of the GGT glycoprotein is not supported by our finding of lack of correlation between them. It is most likely that alpha globulin increases, especially that of alpha-2, resulted from increased synthesis and from the general increase in plasmatic lipoproteins due to alcohol metabolism^7,11,22.

When the hepatocyte is damaged, even without necrosis, the plasma membrane becomes leaky to LDH, AT, and other cytosolic enzymes¹⁴. Elevation of plasma LDH is detected more intensely in hepatotoxic than in viral hepatopathies. Since alcohol is the most important hepatotoxin in medical practice, it could be expected that LDH would be increased in these cases, which was not observed. This finding was concordant those of other authors who tried to utilize LDH as biochemical marker for alcoholic liver damage¹⁷ and indicated that the enzye is not sensitive for detection of hepatocellular damage⁷. The lack of correlation between prevalence of alterations and serum levels of LDH and AT also suggested that the mechanisms promoting elevation of these enzymes in blood due to alcoholic intoxication would be different.

Prevalence of leukocytosis, usually due to neutrophils, was similar to that found in other studies on comparable groups of patients^5,15. Some patients, even asymptomatic ones, may show leukocytosis resulting from appreciable liver cell necrosis³³. Nevertheless, interference of other factors is suggested from observations of lack of correlation between presence or absence of leukocytosis and prevalence of enzymatic alterations or serum levels of hepatic enzymes, TB, and iron. Non-correlation between degree of liver cell damage and white blood cell counts has been already reported²⁵.

CPK was elevated in the majority of patients, with a prevalence higher than the 50% of another study⁴⁵. Only 15% of patients with alcoholic hepatitis showed CPK higher than 100 UI/L²⁵.

Lack of correlation between prevalence and levels of CPK and liver enzymes or TB suggested that CPK alterations did not depend on liver damage but on action of alcohol or its metabolites on skeletal muscles, even without other clinical manifestations compatible with acute alcoholic myopathy. While some authors found frequently normal CPK in chronic alcoholic myopathy, explaining such finding by muscular atrophy without rhabdomyolysis³², others verified that in early phases of myopathy there could be plasma membrane alteration with leakage of muscle cell enzymes^31,44. There are also cases of apparently superimposed syndromes of acute and chronic myopathy²¹.

A significant proportion of alcoholics showed iron deficiency⁸ due to impaired absorption, losses through the gastrointestinal tract, higher plasma depuration, reduced transferrin synthesis by the liver, or action of substances liberated by liver inflammation^{18,23,34,37,39}. In this study, plasma iron concentrations were normal, not reduced in any patient. TCIB and TSI were also normal in the majority of the cases. As in another Brazilian study⁵ with a comparable pattern of alcoholism and clinical characteristics, low prevalence of iron deficiency anemia was the rule. High iron content in the majority of commercial brands of sugarcane liquor²⁶ and the low prevalence of alterations in TCIB and TSI could explain the scarcity of iron deficiency in these studies. On another hand, elevated serum iron has been well correlated with the degree of hepatocellular damage, serum concentrations increasing together with the development of histologically demonstrable liver cell necrosis⁷. The present study showed elevated serum on in cases of hyperbilirubinemia and / or increased ALT, consistent with the proposition that serum iron is related to hepatocyte damage.

Mild elevation of serum amylase was observed in 20% of patients, without apparent influence of amount or duration of alcohol abuse on prevalence of the alteration. During acute pancreatitis crises, the observation of elevation of transaminases, bilirubin and AP^6,24, or of GGT was not rare³⁵, suggesting concomitant liver damage^12,30. In autopsies of 31 chronic alcoholics deceased from causes other than pancreatopathies, pancreatic histologic alterations were found in 23 (75%), 16 of them asymptomatic²⁸. In the present study, correlation between prevalence of hyperamylasemia and hyperbilirubinemia plus the higher serum levels of amylase, AP, and GGT in 25% of patients suggested either direct bile tract damage, which is also a cause of elevated amylase, or bile tract obstruction due to subclinical pancreatitis. On another hand, chronic alcoholics could show hyperamylasemia due to salivary amylase isoenzymes¹³ due to damage of salivary glands¹. If it could be assumed that hyperamylasemia were due to pancreatic aggression, and knowing that only 5% of alcoholics develop symptomatic pancreatitis¹⁰, it is plausible to presume that many alcoholics showing elevated serum amylase would not present symptoms of pancreatic damage.

ACKNOWLEDGMENTS: CNPq. FAPEMIG to RCG.

RESUMO

RHCFAP/2962

BORINI, P. et col. - Indicadores bioquímicos e hematimétricos de inflamação e lesão celular em alcoolistas. Rev. Hosp. Clín. Fac. Med. S. Paulo 54 (2): 53 - 60, 1999.

Indicadores bioquímicos e hematimétricos de inflamação e lesão celular foram correlacionados com bilirrubina e enzimas hepáticas e pancreática em 30 alcoolistas crônicos do sexo masculino internados em hospital psiquiátrico para desintoxicação e tratamento do alcoolismo. A aspartato aminotransferase, alanino aminotransferase, gama-glutamiltransferase, fosfatase alcalina e bilirrubina total estavam alteradas em 90%, 63%, 87%, 23% e 23% dos casos, respectivamente. Entre os indicadores de inflamação (desidrogenase lática, alterada em 16% dos casos; alfa-1 globulina, 24%; alfa-2 globulina, 88% ; contagem de leucócitos, 28%) nenhum estava correlacionado com as alterações da bilirrubina e enzimas hepáticas. A desidrogenase lática revelou-se um teste pouco sensível para detectar lesão hepatocelular ou muscular e as alterações das alfa globulinas parecem dever-se mais ao aumento das lipoproteinas produzidas pelo metabolismo do álcool do que a alterações inflamatórias. Os indicadores de lesão celular (ferro sérico e creatinofosfoquinase) estavam aumentados em 40% e 84% dos casos, respectivamente. O primeiro parece estar cionado a lesão hepática e o último a lesão muscular. Hiperamilasemia foi detectada em 20% dos casos e foi significantemente correlacionada com os níveis da bilirrubina, fosfatase alcalina e gama-glutamiltransferase. Indica-se que lesão de fígado, pâncreas ou glândulas salivares e músculos estriados ocorre em alcoolistas assintomáticos ou oligossintomáticos.

DESCRITORES: Alcoolismo. Fígado. Inflamação. Lesão celular. Enzimas.

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Received for publication on the 07/01/99

From Discipline of Medical Clinic, Marília Medical School, S.P. and the Department of Biology, Biological Science Institute, Federal University of Minas Gerais, M.G.

Publication Dates

• Publication in this collection
  31 Aug 2000
• Date of issue
  Apr 1999

History

• Received
  07 Jan 1999