|Year : 2017 | Volume
| Issue : 2 | Page : 140-145
Serum prolactin level as a biological marker of severity in liver cirrhosis
Fawzy M Khalil1, Mohamed A Elassal1, Ahmed M Hussein1, Mahmoud Rizk1, Mohamed A Awadein2, Eman G Behiry3, Mahmoud M Abd El-Fadil Kelany1
1 Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Benha University, Benha, Egypt
2 Department of Internal Medicine, MUST University, Giza, Egypt
3 Department of Clinical and Chemical Pathology, Faculty of Medicine, Benha University, Benha, Egypt
|Date of Submission||19-Mar-2017|
|Date of Acceptance||10-Apr-2017|
|Date of Web Publication||20-Nov-2017|
Mahmoud M Abd El-Fadil Kelany
Behera, Damnhour, postal/zip code: 22511
Source of Support: None, Conflict of Interest: None
Background Cirrhosis of the liver is a chronic disease that involves the whole organ. In liver cirrhosis, the gonadal axis is affected. Hyperprolactinemia is often present in these patients as well as hyperestrogenemia, both are responsible for the clinical characteristics of feminization.
Patients and methods We investigated 50 patients with cirrhosis. The diagnosis of cirrhosis was based on biochemical evidence and clinical diagnosis including ascites or encephalopathy. Moreover, prognostic indices (Child–Pugh) and prolactin (PRL) levels are assessed.
Results Mean age was 51.94±5.99. Mean Child–Pugh score was 9.16±3.16. Mean PRL level was 18.76±9.14 ng/ml. Patients with hepatic encephalopathy compared with patients without encephalopathy had significantly higher levels of PRL. PRL levels were also significantly related to ascites degree. Mean PRL levels were 13.67 versus 20.05 versus 21.6 ng/ml in patients with first, second, and third degree of ascites, respectively. In regression analysis, PRL level was significantly dependent on Child–Pugh score.
Conclusion PRL level increases significantly with severity of liver disease particularly in patients with ascites and hepatic encephalopathy. High PRL level could therefore be considered as a negative prognostic marker of liver cirrhosis.
Keywords: cirrhosis, liver, prolactin
|How to cite this article:|
Khalil FM, Elassal MA, Hussein AM, Rizk M, Awadein MA, Behiry EG, Abd El-Fadil Kelany MM. Serum prolactin level as a biological marker of severity in liver cirrhosis. Benha Med J 2017;34:140-5
|How to cite this URL:|
Khalil FM, Elassal MA, Hussein AM, Rizk M, Awadein MA, Behiry EG, Abd El-Fadil Kelany MM. Serum prolactin level as a biological marker of severity in liver cirrhosis. Benha Med J [serial online] 2017 [cited 2018 Aug 18];34:140-5. Available from: http://www.bmfj.eg.net/text.asp?2017/34/2/140/218833
| Introduction|| |
Liver cirrhosis is the commonest outcome of the liver parenchymal disease owing to a variety of etiology. Liver cirrhosis is reported to further complicate itself into portal hypertension, liver failure, and hepatocellular carcinoma .
Hepatic encephalopathy and ascites are the commonest complications of liver cirrhosis and are associated with a poor quality of life, increased risk of infection, renal failure, and endocrinal disturbance .
Prolactin (PRL) is a pituitary hormone that stimulates breast development and milk production in women. PRL has no known normal function in men. Physiologically, PRL, is a polypeptide hormone consisting of 199 amino acids. It is regulated by hypothalamic factors. These include PRL-releasing factors and PRL-inhibitory factors ,.
Abnormally higher level of serum PRL hormone in women leads to menstrual dysfunction, amenorrhea, galactorrhea, infertility, hirsutism, and reduced libido whereas the increased level of PRL hormone in men has a direct reversible effect on the hypothalamus, causing secondary hypogonadism which results in erectile dysfunction and reduced libido .
There are many physiological causes of high level of PRL hormone such as pregnancy, puerperium, and breast stimulation. Pathological causes include pituitary tumors, head injury, brain surgery, chronic renal failure, hypothyroidism, Cushing’s syndrome, severe liver disease especially cirrhosis, celiac disease, and polycystic ovarian syndrome ,.
Many hormonal disturbances occur in liver cirrhosis. It was thought that these disturbances were caused mainly by ineffective elimination of hormones by the diseased liver. It is now known that the pathogenesis of disturbed hormonal function in liver cirrhosis is rather more complex, involving disturbed secretion and feedback mechanisms as well. In fact, in liver disease, the metabolic clearance rate of sex steroids for instance is not significantly altered. The most striking hormonal syndrome associated with the liver cirrhosis is the feminization process which occurs in male patients by percentage from 40 to 50% of male patients with cirrhosis .
Feminization process is characterized by a feminine distribution of hair, gynecomastia, palmar erythema, formation of spider nevi, impotence, infertility, and disturbed gonadal function. The role of changes in androgen and estrogen metabolism in causing this process has been elucidated to a large extent and has been the patient of extensive research in recent years .
In the current study, we aimed to assess serum PRL level as a biological marker of severity in liver cirrhosis.
| Patients and methods|| |
This cross-sectional study included 50 patients with chronic liver disease (CLD) who were admitted to Internal Medicine Department and Hepatology, Gastroenterology, and Infectious Diseases Departments, Benha University Hospital, Egypt. A total of 19 patients are females and 31 patients are males. Their ages ranged from 38 to 60 years with a mean±SD of 51.94±5.99. Studied cases are classified into three groups according to modified Child–Pugh score: group 1 included 19 patients with mild liver cirrhosis, group 2 included 15 patients with moderate liver cirrhosis, and group 3 included 16 patients with severe liver cirrhosis.
All patients older than 18 years of age, including both sexes, with proven liver cirrhosis were included. Presence of stigmata of CLD was considered for the support of the diagnosis.
Patients with noncirrhotic hepatitis C virus or hepatitis B virus, patients younger than 18 years old, patients receiving interferon therapy, patients diagnosed with endocrinal disorders, pregnant and lactating women, patients on concomitant psychotropic agents, and patients receiving any drugs that influence PRL level were excluded.
Informed medical consent was obtained from each patient or his/her relative to participate in the study. The study was approved by Scientific Research Committee of Benha University.
All patients were subjected to the following: history taking including age, sex, and past history of risk factors for CLD such as blood transfusion and operations. Moreover, general and local examination was performed on every patient with stress on signs of CLD, for example, jaundice, ascites, palmar erythema, spider nevi, liver size, spleen size, encephalopathy, and lower limb edema. Abdominal ultrasonography is done for all patients.
The following laboratory investigations are done for each patient: 7 ml of venous blood was withdrawn under aseptic precautions after fasting for 10–12 h and distributed as follows: 2 ml of whole blood was put in EDTA vacutainer (violet cap) and mixed up and down gently and is used to measure complete blood count and 3 ml was put in plain tube (red cap) and left to clot and then centrifuged at 2000 rpm for 10 min. The separated serum was divided into two aliquots:
- One is designated for the immediate assay of liver function tests and kidney function test.
- The second aliquot is stored at −20°C for subsequent assay of PRL level.
Moreover, 1.8 ml was put in citrated tube (blue topped) for assay of prothrombin time and international normalized ratio.
- Complete blood count: it was done for all samples using Sysmex KX-21 N (Sysmex; Sysmex Corporation, Wakinohama, Kaigandori, Japan) for red blood cell count, hemoglobin level, hematocrit value, white blood cell count (total and differential), and platelet count.
- Liver function tests: alanine transaminase, aspartate transaminase, total bilirubin, albumin, prothrombin time and concentration, and international normalized ratio were estimated applying the kinetic method and using kit provided by BioSystem S.A. (Barcelona, Spain).
- Kidney function tests: creatinine level was evaluated with the BioSystems reagent kit provided by BioSystems S.A. by modified Jaffe reaction.
- Serological tests for viral markers: HBsAg and HCV-Abs were assessed using enzyme-linked immunosorbent assay technique.
- PRL hormone serum level: PRL was measured quantitatively using human Electro-Chemiluminescence Immunoassay kits provided by Roche Diagnostics GmbH D (reference no. 03203093; Sandhofer, Manheim), with assay range 4.04–15.2 ng/ml, and lower detection limit was 0.047 ng/ml as measured by device named Cobas Auto-Analyzer (Roche, Mannheim, Germany).
Biotinylated specific monoclonal antibody against PRL forms complex with samples. The well had been precoated with human PRL monoclonal antibody. The contents of the well were then incubated. Thereafter, PRL antibodies labeled with ruthenium complex and combined with streptavidin-coated microparticles were added to form an immune complex, and become coated to solid phase by biotin–streptavidin complex. Incubation was repeated, and microparticles are magnetically captured on surface of electrode. Application of voltage to electrode induces chemiluminescence emission measured by photomultiplier.
Severity of liver cirrhosis was determined by Modified Child–Pugh score ([Table 1]).
The collected data were summarized in terms of mean±SD and range for quantitative data and frequency and percentage for qualitative data. Comparisons between the different study groups were carried out using the χ2 test and Fisher’s exact test to compare proportions as appropriate. The Mann–Whitney test (z) was used to compare two groups regarding nonparametric data, and the Kruskal–Wallis test (χ2) was used to compare more than two groups. The Spearman correlation coefficient (ρ) was used to assess the correlation between serum PRL levels and estimated parameters. Receiver operating characteristics analysis was carried out to evaluate the diagnostic performance of serum PRL levels as a predictor for liver cirrhosis severity and hepatic encephalopathy. The best cut-off point and the corresponding sensitivity and specificity, positive predictive value, negative predictive value, and area under the curve were estimated. All statistical analyses were carried out in STATA/SE (version 11.2 for Windows; STATA Corporation, College Station, Texas, USA).
| Results|| |
This study included 50 patients with age ranging from 38 to 60 years with mean±SD of 51.94±5.99 years; there were 31 (62%) male patients and 19 (38%) female patients. PRL level was 5.5–39 ng/ml, with mean±SD of 18.76±9.14 ng/ml. The albumin level was from 1.2 to 4.2 mg/dl, with mean±SD of 3.08±0.85 g/dl. Total bilirubin level was from 1.2 to 6.8 mg/dl, with mean±SD of 2.6±1.3 mg/dl. Prothrombin time was from 2.9 to 18.5 s, with mean±SD of 8.9±5.54 s. Creatinine level was from 0.7 to 6 mg/dl, with mean±SD of 2.25±1.21 mg/dl. Portal vein diameter by ultrasound ranged from 10–19 cm, with mean±SD of 12.19±1.74 cm. Child–Pugh score level was from 5 to 14, with mean±SD of 9.16±3.16.
The current study revealed that there was a statistically significant difference between severity of cirrhosis and encephalopathy grading.
There was a highly statistically significant difference between severity of cirrhosis and degree of ascites, PRL level, albumin level, bilirubin level, prothrombin time, and Child–Pugh score.
There was no statistically significant difference between severity of cirrhosis and portal vein diameter, creatinine level, sex, or age.
There was highly statistical significant increase regarding PRL level in moderate and severe liver cirrhosis than mild liver cirrhosis.
There was a highly statistical significant decrease regarding albumin level in severe liver cirrhosis than mild and moderate liver cirrhosis.
There was a highly statistical significant increase regarding bilirubin level in severe liver cirrhosis than mild and moderate liver cirrhosis.
There was a highly statistical significant increase regarding prothrombin time in severe liver cirrhosis than mild and moderate liver cirrhosis.
There was a highly statistical significant increase regarding Child–Pugh score in moderate and severe liver cirrhosis than mild liver cirrhosis ([Table 2]).
|Table 2 Comparisons between patients with severe, moderate, and mild liver cirrhosis regarding baseline variables|
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There was a statistically significant negative correlation between serum PRL level and albumin level, and there was a statistically significant positive correlation between serum PRL level and bilirubin level, prothrombin time, and cirrhosis severity. Moreover, a statistically highly significant positive correlation was found between serum PRL level and encephalopathy grades ([Table 3]).
|Table 3 Correlation between serum prolactin level (ng/ml) and estimated parameters|
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Statistically highly significant differences were found in the serum PRL level and sex, statistically highly significant differences were found in the serum PRL level and hepatic encephalopathy grades, and statistically significant differences in the serum PRL level and Child–Pugh grades. There was a highly statistical significant increase regarding PRL level in grades 3 and 4 encephalopathy than no encephalopathy. There was a statistical significant increase regarding PRL level in Child–Pugh grade C than Child–Pugh grade A ([Table 4] and [Table 5]).
|Table 4 Variations in the serum prolactin levels by patients’ characteristics|
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|Table 5 Diagnostic accuracy with serum prolactin in predicting severe/moderate liver cirrhosis|
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By using receiver operating characteristics curve for serum PRL level as a predictor for severe/moderate liver cirrhosis, it was found that the cut-off point was 18.8 ng/ml, the sensitivity was 67.74%, the specificity was 78.95, the positive predictive value was 84%, and the negative predictive value was 60% ([Figure 1]).
|Figure 1 Receiver operating characteristics analysis for serum prolactin level as a predictor for severe/moderate liver cirrhosis.|
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| Discussion|| |
Cirrhosis is a gradually developing, chronic disease of the liver which always involves the organ as a whole. It is the irreversible consequence and final stage of various CLDs of different etiology or the result of long-term exposure to various factors. The extent of the morphological changes depends on the cause and stage of cirrhosis. Accordingly, there is a wide spectrum of morphological findings and clinical symptoms. The variations of this disease range from symptom-free conditions, non-characteristic complaints, and different laboratory findings through to life-threatening complications .
The polypeptide human prolactin hormone is synthesized and secreted from the lactotrophic cells of the anterior pituitary gland. The human PRL molecule is arranged in a single chain of 199 amino acids with three intramolecular disulfide bonds .
The gonadal axis is notably affected in liver cirrhosis. Hyperprolactinemia is often present in these patients as well as hyperestrogenemia, both responsible for the clinical characteristics of feminization. Hyperprolactinemia and hyperestrogenemia can contribute to the genesis of hypogonadism .
The present study aims to assess serum PRL level as a biological marker of severity in liver cirrhosis.
The current study showed highly significant relation between severity of cirrhosis and PRL level (P<0.001), where serum PRL hormone level increases with the severity of liver cirrhosis, and this increasing of PRL is attributed mainly to the decrease in dopamine levels in the tuberoinfundibular tract. Hormonal disturbance in cirrhosis has been evaluated by few researchers, and the studies have been established lower T3 and cortisol levels with raised PRL in the serum .
Decompensated liver function leads to an alteration in the type of amino acids entering the central nervous system. Concentration of circulating aromatic amino acids has been found to increase, leading to an increase in the synthesis of false neurotransmitters such as phenylethanolamine and octopamine .
These false neurotransmitters may inhibit the dopamine release contributing to hyperprolactinemia. Hyperprolactinemia leading to hypogonadism in patients with cirrhosis .
This consistent with the study carried out by Ferrini et al.  who reported that increased estradiol and PRL levels and decreased serum testosterone level were observed in patients with liver cirrhosis, compared with normal person. Low testosterone and high PRL levels were determined to be correlated with the cirrhosis severity. This consistent with the study reported by Mukherjee et al.  where severity of hepatic cirrhosis was positive correlation with level of serum PRL.
There was significant negative correlation between serum PRL level and albumin, where r=−0.29 and P=0.04. This is consistent with the study reported by Arafa et al.  whereas there was a significant negative correlation between serum PRL concentration and serum albumin.
There was significant positive correlation between serum PRL level and severity of cirrhosis, where r=0.42 and P=0.003. This is consistent with the study reported by Arafa et al.  where serum level of PRL significantly increased with progression of liver disease from Child A to Child C .
There was a highly significant positive correlation between serum PRL level and encephalopathy grades, where r=0.71 and P less than 0.001. This is consistent with the study reported by Arafa et al.  that showed significantly increased serum level of PRL in patients with HE more than patients with cirrhosis without HE, and its level was significantly increased with progression of liver disease from Child A to Child C and increased with severity of HE.
| Conclusion|| |
PRL levels increase significantly with severity of liver disease particularly in patients with ascites and hepatic encephalopathy. High PRL level could therefore be considered as a negative prognostic marker of liver cirrhosis.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Song JY, Jung SJ, Park CW, Sohn JW, Kim WJ, Kim MJ et al.
Prognostic significance of infection acquisition sites in spontaneous bacterial peritonitis: nosocomial versus Community Acquired. J Korean Med Sci 2006; 21:666–671.
Fullwood D, Sargent S. Complications in acute liver failure: managing hepatic encephalopathy and cerebral oedema. Gastrointest Nurs 2014; 12:27–34.
Cho KR, Jo KI, Shin HJ. Bromocriptine therapy for the treatment of invasive prolactinoma: the single institute experience. Brain Tumor Res Treat 2013; 1:71–77.
Maiter D, Delgrange E. Therapy of endocrine disease: the challenges in managing giant prolactinomas. Eur J Endocrinol 2014; 170:213–227.
Shindel AW. Hormone abnormalities are not related to the erectile dysfunction and decreased libido found in many men with infertility. Yearbook Urol 2014; 2014:150–151.
Kars M, Dekkers OM, Pereira AM, Romijn JA. Update in prolactinomas. Neth J Med 2010; 68:104–112.
Cheng J, Kozikowski AP. We need 2C but not 2B: developing serotonin 2C (5-HT 2C) receptor agonists for the treatment of CNS disorders. ChemMedChem 2015; 10:1963–1967.
Patel N, Munoz SJ. Bone disease in cirrhosis. Clin Liver Dis 2015; 6:96–99.
Nieddu M, Boatto G, Dessi G. Determination of four thiophenethylamine designer drugs (2C-T-4, 2C-T-8, 2C-T-13, 2C-T-17)in human urine by capillary electrophoresis/mass spectrometry. Rapid Commun Mass Spectrom 2010; 24:2357–2362.
King LY, Canasto-Chibuque C, Johnson KB, Yip S, Chen X, Kojima K et al.
A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut 2015; 64:1296–1302.
Parke CY, Martin P. Renal dysfunction in cirrhosis. Clin Liver Dis 2015; 5:150–153.
Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev 2000; 80:1523–1631.
Arafa M, Besheer T, El-Kanneshy G, El-hussiny MA, Rakha EB. Features of hormonal disturbances in cirrhotic patients with hepatic encephalopathy. Euroasian J H Gastroentrol 2012; 2:84–89.
Velissaris D, Karanikolas M, Karamouzos P, Polychronopoulos P, Kalogeropoulos A. Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy. World J Gastroenterol 2008; 14:4190–4195.
Als-Nielsen B, Korets RL, Kjaergard LL, Gluud C. Branched chain amino acid for hepatic encephalopathy. Cochrane Database Sys Rev 2003; 2:19–39.
Karaginnis A, Harsoulis F. Gonadal dysfunction in systemic. Eur J Endocrinol 2005; 152:501–513.
Ferrini M, Wang C, Swerdloff RS, Sinha Hikim AP, Rajfer J, Gonzalez-Cadavid NF. Aging-related increased expression of inducible nitric oxide synthase and cytotoxicity markers in rat hypothalamic regions associated with male reproductive function. Neuroendocrinology 2001; 74:1–11.
Mukherjee S, Kar M, Dutta S. Observation on serum prolactin in hepatic cirrhosis. J Indian Med Assoc 1991; 89:307–308.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]