Drug and AlcoholDependence,
Elsevier Scientific Publishers
91
25 (1%)) 91-95
Ireland Ltd.
Clinical and prognostic value of serum procollagen chronic alcoholic liver disease
levels in
E. Gonzblez-Reimers’, M.M. Brajin-Rodriguez’, F. Rodriguez-Moreno”, F. Santolaria-Fernbndez”, N. Batista-L6peza, H. Alvarez-Argiiellesb, A. Milena’, A. Rodriguez-Hernhdez’ “Departments
of Internal Medicine, bPathological Anatomy
and CPhysiology, University Hospital of the Canaries, La Laguna,
TQnQtifQ (Spain)
(Received October 3rd, 19891
Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells, including Ito cells, transitional cells, myofibroblasts and hepatocytes. Synthesis of collagen fibrils follows a complex metabolic pathway with intermediate products such as type III procollagen (III-PC). Serum levels of III-PC may reflect the activity of the fibrogenetic process. We analysed the relationship between the serum levels of III-PC W-terminal peptidel and diverse clinical, biochemical and histological parameters of ‘77alcoholic patients (27 cirrhoticsl, comparing them with those of 15 age- and sex-matched controls. A highly significant difference was obtained between controls and patients (P < 0.00011, but no differences were observed between cirrhotics and non-cirrhotics. Serum III-PC significantly correlated with clinical and biochemical data of liver function derangement (prothrombin activity, serum albumin, bilirubin, gynecomastia, ascites, encephalopathy, edema, splenomegalyl; with the duration of ethanol addiction and with MCV. Sixty patients were followed up for a period ranging between 3 and 1056 days (mean = 356 days); 9 of them died. Patients with III-PC levels above 38 nglml had a significantly higher mortality Cp = 0.0061 than those with levels under 38 (log rank test). Thus, serum III-PC may be a useful tool in the clinical evaluation and prognostic assessment of patients with chronic alcoholic liver disease. Key words: alcoholism; cirrhosis; prognosis; procollagen
Introduction Ethanol intoxication of the liver leads to steathosis and cirrhosis [l]. The relative organspecificity of the drug and the absence of a feedback mechanism to adapt the metabolic rate of ethanol to the functional status of the liver explain the nocive effect of ethanol on the viscera [2]. Ethanol-mediated redox changes within the liver cell and the toxic effect of acetaldehyde lead to accumulation of fat, protein and water within the hepatocytes, and to progressive fibrosis, which ultimately results
Correspondence
to: E. Gonzalez-Reimers.
0376.8716/90/$03.50 0 1990 Elsevier Scientific Publishers Printed and Published in Ireland
in the development of cirrhosis [3]. Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells [4], including Ito cells, transitional cells, myofibroblasts and also hepatocytes [5]. Synthesis of collagen fibrils follows a complex metabolic pathway, in which intermediate proteins such as procollagen are produced [6]. Among the various types of collagen, type III is the most abundantly synthetized in alcoholic liver cirrhosis [7]. Therefore serum type III procollagen is elevated in this disease, reflecting the rate of liver fibrogenesis [8], although necrosis, a characteristic feature of liver cirrhosis, may lead to a certain degree of leakage of procollagen into the bloodstream [9]. Ireland Ltd.
92
Several authors have analysed the significance of serum procollagen levels in a variety of chronic liver diseases [lo- 131. Which information that this parameter may provide regarding ongoing fibrosis has been studied in 22 cases of chronic liver disease, particularly chronic active hepatitis [13]. In the present study we analysed the relationship between serum procollagen levels and several clinical and biological parameters of 77 patients affected by chronic alcoholic liver disease, and also, the prognostic significance of this parameter regarding mortality.
described [14]. The presence of mononuclear and polymorphonuclear infiltrates, and of erosive necrosis were graded in two categories: absent-mild vs. moderate-severe. Sixty of the 77 patients were followed up for a mean period of 356 days (range: 3- 10561; 9 of them died. We have analysed the prognostic value of serum III-PC levels comparing, by means of the Kaplan and Meier curves and logrank test the survival rates of patients with serum III-PC greater or lower than the mean (~1,x + 0.75 S.D., 2 + S.D., J: + 1.25 S.D., 2 + 1.5 S.D.
Subjects and Methods
Results
Seventy-seven consecutively admitted alcoholic patients (70 males and 7 females) participated in the study. Twenty-seven were affected by liver cirrhosis, and 50 by non-cirrhotic liver disease. The diagnosis was histologically assessed in 51 cases. Serum procollagen was also determined in 15 healthy controls (age- and sex-matched) who did not consume ethanol-containing beverages. At admission to hospital, the following data were recorded: years of alcohol addiction; daily amount of ethanol consumption; mean corpuscular volume (MCV); prothrombin activity; serum ALAT, ASAT, GGT; alkaline phosphatase; proteins; albumin; gammaglobulin; a2globulin and serum bilirubin; presence or not of jaundice, ascites, encephalopathy, collateral circulation, gynecomastia, palmar erythema, splenomegaly or hepatomegaly. N-terminal serum type III procollagen (IIIPC) was determined by radioimmunoassay in all the patients and the controls. Statistical analysis: All patients vs. controls, by Student’s t-test and Pearson’s single correlation; controls vs. cirrhotics and non-cirrhotic patients by analysis of variance. The following histological and histomorphometrical data were recorded: hepatocyte and nuclear areas, both of the pericentral and periportal regions: total amount of fat and percentage of fibrosis, using a WIDS II image analyser and following the method previously
Results are shown in Table I and Figs. 1 and 2. Highly significant differences were obtained between controls and patients Cp < 0.00011, but not between cirrhotics and non-cirrhotics. There was a significant relationship between serum procollagen and MCV (P = 0.0111, and a 50
50
-2.9
:O. 006 40
7
30
2 ; LO 10
0
SO
50
t=2.09 pzo.043
40
40
Fig. 1. Serum conditions.
procollagen
t=2.56 p:O. 032 I
levels
T
in different
clinical
93
Table I.
Correlations
between serum procollagen levels and different clinical and biological P
r Alcohol (years) Hematocrit MCV Total Bilir. Cholesterol
0.4 -0.4 0.35 0.25 0.21
0.09 0.003 0.01 0.032 NS
Alcohol (g/day) Hemoglobin Prothrombin Direct Bilir. BUN
NS
ALAT
0.09 0.08 - 0.4 0.03 - 0.1 - 0.1
NS NS 0.001 NS NS NS
GGT LDH Albumin Q/oFibrosis Hepatocyte area Nuclear area
t
P
0.97 0.45
NS NS
Creatinin
0.09
ASAT Alk. Phosphat. Total Proteins Gammaglobulin % Fat Fat droplet
Ero. necrosis Neutroph. inf.
nearly significant relationship with the years of ethanol addiction (0.1 > P > 0.05). Inverse relationships were obtained between procollagen and prothrombin activity P < 0.0011, serum albumin P < 0.021, serum proteins P < 0.0051,
r
P
0.02 - 0.38 - 0.38 0.03 0.07
NS 0.006 0.001 NS NS
0.06
Nononuel. infilt
parameters.
NS
0.05 0.06 - 0.27 0.11 0.02 0.05
NS NS 0.019 NS NS NS
t
P
0.98
NS
and serum crZglobulin (P < 0.011, whereas a direct one was established between procollagen and serum bilirubin P < 0.051. Serum procollagen levels were higher in patients with gynecomastia (t = 3.32, P
Elsevier Scientific Publishers
91
25 (1%)) 91-95
Ireland Ltd.
Clinical and prognostic value of serum procollagen chronic alcoholic liver disease
levels in
E. Gonzblez-Reimers’, M.M. Brajin-Rodriguez’, F. Rodriguez-Moreno”, F. Santolaria-Fernbndez”, N. Batista-L6peza, H. Alvarez-Argiiellesb, A. Milena’, A. Rodriguez-Hernhdez’ “Departments
of Internal Medicine, bPathological Anatomy
and CPhysiology, University Hospital of the Canaries, La Laguna,
TQnQtifQ (Spain)
(Received October 3rd, 19891
Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells, including Ito cells, transitional cells, myofibroblasts and hepatocytes. Synthesis of collagen fibrils follows a complex metabolic pathway with intermediate products such as type III procollagen (III-PC). Serum levels of III-PC may reflect the activity of the fibrogenetic process. We analysed the relationship between the serum levels of III-PC W-terminal peptidel and diverse clinical, biochemical and histological parameters of ‘77alcoholic patients (27 cirrhoticsl, comparing them with those of 15 age- and sex-matched controls. A highly significant difference was obtained between controls and patients (P < 0.00011, but no differences were observed between cirrhotics and non-cirrhotics. Serum III-PC significantly correlated with clinical and biochemical data of liver function derangement (prothrombin activity, serum albumin, bilirubin, gynecomastia, ascites, encephalopathy, edema, splenomegalyl; with the duration of ethanol addiction and with MCV. Sixty patients were followed up for a period ranging between 3 and 1056 days (mean = 356 days); 9 of them died. Patients with III-PC levels above 38 nglml had a significantly higher mortality Cp = 0.0061 than those with levels under 38 (log rank test). Thus, serum III-PC may be a useful tool in the clinical evaluation and prognostic assessment of patients with chronic alcoholic liver disease. Key words: alcoholism; cirrhosis; prognosis; procollagen
Introduction Ethanol intoxication of the liver leads to steathosis and cirrhosis [l]. The relative organspecificity of the drug and the absence of a feedback mechanism to adapt the metabolic rate of ethanol to the functional status of the liver explain the nocive effect of ethanol on the viscera [2]. Ethanol-mediated redox changes within the liver cell and the toxic effect of acetaldehyde lead to accumulation of fat, protein and water within the hepatocytes, and to progressive fibrosis, which ultimately results
Correspondence
to: E. Gonzalez-Reimers.
0376.8716/90/$03.50 0 1990 Elsevier Scientific Publishers Printed and Published in Ireland
in the development of cirrhosis [3]. Liver fibrogenesis involves the synthesis of collagen fibrils and proteoglycans by various types of liver cells [4], including Ito cells, transitional cells, myofibroblasts and also hepatocytes [5]. Synthesis of collagen fibrils follows a complex metabolic pathway, in which intermediate proteins such as procollagen are produced [6]. Among the various types of collagen, type III is the most abundantly synthetized in alcoholic liver cirrhosis [7]. Therefore serum type III procollagen is elevated in this disease, reflecting the rate of liver fibrogenesis [8], although necrosis, a characteristic feature of liver cirrhosis, may lead to a certain degree of leakage of procollagen into the bloodstream [9]. Ireland Ltd.
92
Several authors have analysed the significance of serum procollagen levels in a variety of chronic liver diseases [lo- 131. Which information that this parameter may provide regarding ongoing fibrosis has been studied in 22 cases of chronic liver disease, particularly chronic active hepatitis [13]. In the present study we analysed the relationship between serum procollagen levels and several clinical and biological parameters of 77 patients affected by chronic alcoholic liver disease, and also, the prognostic significance of this parameter regarding mortality.
described [14]. The presence of mononuclear and polymorphonuclear infiltrates, and of erosive necrosis were graded in two categories: absent-mild vs. moderate-severe. Sixty of the 77 patients were followed up for a mean period of 356 days (range: 3- 10561; 9 of them died. We have analysed the prognostic value of serum III-PC levels comparing, by means of the Kaplan and Meier curves and logrank test the survival rates of patients with serum III-PC greater or lower than the mean (~1,x + 0.75 S.D., 2 + S.D., J: + 1.25 S.D., 2 + 1.5 S.D.
Subjects and Methods
Results
Seventy-seven consecutively admitted alcoholic patients (70 males and 7 females) participated in the study. Twenty-seven were affected by liver cirrhosis, and 50 by non-cirrhotic liver disease. The diagnosis was histologically assessed in 51 cases. Serum procollagen was also determined in 15 healthy controls (age- and sex-matched) who did not consume ethanol-containing beverages. At admission to hospital, the following data were recorded: years of alcohol addiction; daily amount of ethanol consumption; mean corpuscular volume (MCV); prothrombin activity; serum ALAT, ASAT, GGT; alkaline phosphatase; proteins; albumin; gammaglobulin; a2globulin and serum bilirubin; presence or not of jaundice, ascites, encephalopathy, collateral circulation, gynecomastia, palmar erythema, splenomegaly or hepatomegaly. N-terminal serum type III procollagen (IIIPC) was determined by radioimmunoassay in all the patients and the controls. Statistical analysis: All patients vs. controls, by Student’s t-test and Pearson’s single correlation; controls vs. cirrhotics and non-cirrhotic patients by analysis of variance. The following histological and histomorphometrical data were recorded: hepatocyte and nuclear areas, both of the pericentral and periportal regions: total amount of fat and percentage of fibrosis, using a WIDS II image analyser and following the method previously
Results are shown in Table I and Figs. 1 and 2. Highly significant differences were obtained between controls and patients Cp < 0.00011, but not between cirrhotics and non-cirrhotics. There was a significant relationship between serum procollagen and MCV (P = 0.0111, and a 50
50
-2.9
:O. 006 40
7
30
2 ; LO 10
0
SO
50
t=2.09 pzo.043
40
40
Fig. 1. Serum conditions.
procollagen
t=2.56 p:O. 032 I
levels
T
in different
clinical
93
Table I.
Correlations
between serum procollagen levels and different clinical and biological P
r Alcohol (years) Hematocrit MCV Total Bilir. Cholesterol
0.4 -0.4 0.35 0.25 0.21
0.09 0.003 0.01 0.032 NS
Alcohol (g/day) Hemoglobin Prothrombin Direct Bilir. BUN
NS
ALAT
0.09 0.08 - 0.4 0.03 - 0.1 - 0.1
NS NS 0.001 NS NS NS
GGT LDH Albumin Q/oFibrosis Hepatocyte area Nuclear area
t
P
0.97 0.45
NS NS
Creatinin
0.09
ASAT Alk. Phosphat. Total Proteins Gammaglobulin % Fat Fat droplet
Ero. necrosis Neutroph. inf.
nearly significant relationship with the years of ethanol addiction (0.1 > P > 0.05). Inverse relationships were obtained between procollagen and prothrombin activity P < 0.0011, serum albumin P < 0.021, serum proteins P < 0.0051,
r
P
0.02 - 0.38 - 0.38 0.03 0.07
NS 0.006 0.001 NS NS
0.06
Nononuel. infilt
parameters.
NS
0.05 0.06 - 0.27 0.11 0.02 0.05
NS NS 0.019 NS NS NS
t
P
0.98
NS
and serum crZglobulin (P < 0.011, whereas a direct one was established between procollagen and serum bilirubin P < 0.051. Serum procollagen levels were higher in patients with gynecomastia (t = 3.32, P
