800 Endocrine Care
Serum Prolactin in Advanced Chronic Liver Disease
Affiliations
Key words
▶ prolactin ● ▶ liver cirrhosis ● ▶ Child–Pugh score ●
C. Ress1, P.-A. Maeser1, A. Tschoner1, L. Loacker2, K. Salzmann1, G. Staudacher1, A. Melmer1, H. Zoller3, W. Vogel3, A. Griesmacher2, H. Tilg1, I. Graziadei3, 4, S. Kaser1 1
Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria Central Institute for Medical and Chemical Laboratory Diagnostics, Medical University Innsbruck, Innsbruck, Austria 3 Department of Internal Medicine II, Medical University Innsbruck, Innsbruck, Austria 4 Division of Internal Medicine, Hospital Hall in Tirol, Hall, Austria 2
Abstract
▼
Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etiologies. Eighteen out of 178 patients – 7 females and 11 males – displayed elevated serum prolactin levels. When patients were excluded who
Introduction received 25.01.2014 accepted 07.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375612 Published online: May 9, 2014 Horm Metab Res 2014; 46: 800–803 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence S. Kaser, MD Department of Internal Medicine I Medical University Innsbruck Anichstrasse 35 6020 Innsbruck Austria Tel.: + 43/512/504 81407 Fax: + 43/512/504 28539 [email protected]
▼
Hyperprolactinemia is a common endocrine disorder that is frequently associated with hypogonadism, infertility, and bone loss in the long term [1]. All these clinical entities are commonly found in liver cirrhotics [2]. As an example, osteoporosis and increased fracture risk have been shown to be a clinically relevant problem in liver transplant recipients, and osteoporosis is not only found after but even prior to liver transplantation [3, 4]. There are several physiological as well as also pathological conditions that cause hyperprolactinemia: physiologically, prolactin levels are elevated in pregnancy and during nursing. Apart from that, disorders such as pituitary tumors, primary hypothyreoidism, conditions of neurogenic stimulation such as chest wall injury, renal failure or hypophysitis might cause hyperprolactinemia as well. Additionally, intake of several medications including antipsychotics, antidepressants, metoclopramide, and other gastric motility agents as well as some antihypertensive
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.
drugs are associated with mild to moderate hyperprolactinemia [1]. Chronic liver disease has also been suggested to cause hyperprolactinemia for a long time [1]. The idea goes back to 1978 when Morgan [5] found that prolactin levels were unexpectedly high in patients with chronic liver disease. Additionally, prolactin levels were shown to be elevated in cirrhotics with Child– Pugh Class C suggesting that hyperprolactinemia was correlated with stage of liver disease [6]. Mechanistically, direct and indirect effects of ethanol on lactotrophic cells and dopamine metabolism [7, 8] as well as increased estrogen levels have been suggested to contribute to hyperprolactinemia [9–11]. However, Zietz and colleagues found that prolactin levels were independent of etiology of liver disease [6, 12]. In contrast to the studies of Morgan et al. and Zietz et al., Seehofer and colleagues reported similar normal prolactin levels before and after transplantation [12]. Moreover Velissaris and colleagues [13] found no association between prolactin levels and severity of liver cirrhosis as estimated by the Child–Pugh Score.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
In this study, we set out to investigate prevalence and predictors of hyperprolactinemia in patients with liver cirrhosis.
Subjects and Methods
▼
Study population A cohort of 178 adult patients suffering from liver cirrhosis of different etiologies who were evaluated for liver transplantation between 2008 and 2011 at the University Hospital Innsbruck were included in the study. Etiologically, disorders were classified into chronic viral hepatitis, alcoholic or nonalcoholic fatty liver disease, autoimmune disorders, inherited metabolic liver diseases, and cryptogenic liver diseases. Patients with acute liver failure, patients who had undergone liver transplantation before as well as one patient with Morbus Cushing were excluded from the study. Additionally, patients with cholangiocarcinoma, mucoviscidosis, and polycystic liver disease were excluded from the study. At the time of investigation, all patients have been abstinent from alcohol for at least 6 months. The study was approved by the local ethics committee and all patients gave their informed written consent.
9.3 ng/ml, IQR (7.1–15.5), males: median: 8.7 ng/ml, IQR (6.35– 12.5), p = 0.02]. In total, 7 female and 11 male patients displayed elevated serum prolactin levels [females: median 41.6 ng/ml, IQR (38.4–79.0), males: median: 19.4 ng/ml, IQR (18.8–23.6)]. From these 18 patients, 6 patients had disorders and 3 were treated with drugs that are well known to potentially cause hyperprolactinemia: 4 patients suffered from advanced chronic kidney disease (stages III–V) and 2 from overt hypothyroidism (TSH > 4 mU/l), 1 patient received opiates for pain relief, 1 patient was under systemic glucocorticoid, and 1 under antidepressant therapy (serotonine reuptake inhibitor), respectively [1, 15]. Additionally, 6 patients received treatment with aldosterone antagonists. As the renin angiotensin system has been discussed to potentially affect dopamine and prolactin metabolism [16, 17], these patients were also considered to have a confounding factor that eventually influences prolactin levels. Accordingly, only 3 male patients with hyperprolactinemia had no disorder or received any treatment that potentially affects prolactin levels. Two patients with hyperprolactinemia without presence of confounding factors were classified as chronic liver disease of Child–Pugh class C and one of Child–Pugh class B.
Etiology of liver disease Laboratory measurements Blood samples were drawn after an overnight fast and rapidly processed or stored at − 80 °C after centrifugation. Liver function tests, renal function tests, thyroid-stimulating hormone levels, bilirubin, INR, and albumin levels were measured by commercially available kits. Serum prolactin levels were determined by a solid-phase 2 side chemoluminescent immunometric assay (Immulite 2000 Prolactin, Siemens). The presence of macropolactinemia was excluded by preparation of samples using the polyethylene glycol precipitation method [14]. Normal ranges were 1.9–25 ng/ml for adult females and 2.5–17 ng/ml for adult males.
▶ Table 1. To test whether Etiologies of liver disease are shown in ● etiology of liver disease affects serum prolactin levels, patients suffering from alcoholic liver disease (ALD) (n = 62), nonalcoholic steatohepatitis (NASH) (n = 32), viral hepatitis (n = 55), or autoimmune disorders (n = 25) were analyzed. Patients with cryptogenic liver disease (n = 3) or inherited metabolic liver disease (n = 1) were not included in this analysis. Serum prolactin levels were similar in all groups [ALD: median: 9.7 ng/ml, IQR (7.0–13.7), NAFLD: median: 7.8 ng/ml, IQR (6.0–10.5), viral hepatitis: median: 8.8 ng/ml, IQR (6.2–14.4), autoimmune disorders: median: 8.6 ng/ml, IQR (6.6–12.5), p = 0.45].
Stage of liver disease Statistical analysis Descriptive data are expressed as means ± SD. Statistical significance was inferred at a p-value of less than 0.05. The significance of differences in means between more than 2 groups was tested by ANOVA analysis with the Bonferroni correction. Shapiro-Wilk analysis was used to test for normality. Not normally distributed data were log-transformed in order to achieve normality for further analysis in which case data are presented as median and interquartile range (IQR) shown as range between the first and the third quartile except for male patients with hyperprolactinemia without confounding factors (median, min/max). Clinical characteristics are shown as means ± SD. A multiple stepwise linear regression analysis was done by entering the independent variable with the highest partial correlation coefficient at each step and a probability of F to enter ≤ 0.050 and a probability of F to remove ≥ 0.100. Statistical analysis was performed using the statistical software package for Windows Version 21 (SPSS, Chicago, IL, USA).
Results
▼
Prevalence of hyperprolactinemia Clinical characteristics of all study patients (n = 178) are shown ▶ Table 1. As expected, serum prolactin levels were signifiin ● cantly higher in female patients than in males [females: median:
Stage of liver disease was classified by the Child–Pugh Score. As ▶ Table 1, 35 patients were defined as Child–Pugh shown in ● class A, 98 patients as Child–Pugh class B, and 45 patients as Child–Pugh class C, respectively. Prolactin levels significantly increased with progression of liver disease as estimated by the ▶ Fig. 1); however, Child–Pugh score (classes A–C) (p < 0.01) (● Table 1 Clinical characteristics of study patients. Parameter (normal range) Age (years) Etiology of liver disease, n ALD NASH Viral hepatitis Autoimmune disorders Inherited metabolic liver disease Cryptogenic Creatinine, mg/dl (f: < 0.95, m: < 1.17) INR (PT), % (70–120) Albumin, g/l (41.9–53.5) Bilirubin, μmol/l ( < 22.1) Child–Pugh Score (A/B/C)
Females
Males
(n = 44)
(n = 134)
54.1 ± 11.0
58.2 ± 8.5
12 7 10 14 – 1 0.92 ± 0.38 1.49 ± 0.76 35.92 ± 6.91 89.90 ± 130.04 5/27/12
50 25 45 11 1 2 0.96 ± 0.48 1.53 ± 0.90 35.27 ± 6.22 81.40 ± 123.80 30/71/33
Values are means ± SD ALD: Alcoholic liver disease; NASH: Nonalcoholic steatohepatitis
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
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Endocrine Care 801
Fig. 1 Box- and whisker plot of serum prolactin levels for Child–Pugh classes groups. Serum prolactin levels significantly increased with class of chronic liver disease estimated by the Child–Pugh Score (p < 0.01). Median, IQR (box), ° outliers > 1 SD, * outliers > 2 SD.
significant differences in prolactin levels between the Child– Pugh classes were only found in males but not in females (data not shown).
Regression analysis When a multiple linear stepwise regression analysis including ascites, encephalopathy, albumin, bilirubin, and INR as independent variables was performed, ascites remained the only significant predictor of serum prolactin levels (R2: 0.054, β coefficient: 0.232, p < 0.01). When adding creatinine as an independent variable, ascites and creatinine were significant predictors of serum prolactin levels (F = 10.24, R2: 0.102; p = 0.02; ascites: β coefficient: 0.232, p < 0.01, creatinine: β coefficient: 0.217, p < 0.01).
Discussion
▼
Hyperprolactinemia is a prevalent endocrine disorder of varying etiology that has been shown to have long-term impact on bone health and sexual hormone metabolism. Decades ago it was reported that hyperprolactinemia is common in liver cirrhosis [5, 18]. As a result, liver cirrhosis is now a well-accepted etiology of hyperprolactinemia [19, 20]. While its effects on lactation und the reproductive function have widely been investigated, newer studies have also suggested tumor growth potency as well as several autocrine or paracrine actions by locally produced prolactin [21]. These different functions of prolactin are mediated by its receptor which is expressed in different tissues and cells such as lymphoid cells, endometrium, prostate and adipocytes [22]. Recently, prolactin was shown to accelerate liver regeneration in rodents [23]. In other studies it was shown that expression and distribution of prolactin receptors are different in cirrhotic, fibrotic, and healthy livers in both rodents and humans [24, 25]. Taken together these data suggest hepatic effects of prolactin, putting another complexion on hyperprolactinemia in advanced liver disease.
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
In our study, only 18 out of 178 patients had elevated serum prolactin levels. Thus, our data suggest that the prevalence of hyperprolactinemia in patients with advanced liver disease lies between the frequency reported in healthy adults (0.4 %) and the one in women with reproductive disorders (9–17 %) [26]. When excluding patients who took medications that are known to potentially cause hyperprolactinemia or who had co-morbidities that per se might be associated with hyperprolactinemia, only 3 out of 55 patients had hyperprolactinemia. We thus conclude from our findings that hyperprolactinemia in liver cirrhosis primarily results from associated diseases such as renal failure or is drug-induced while chronic liver disease itself seems not to be a common cause of hyperprolactinemia. The clinical relevance of mild hyperprolactinemia in these patients remains unclear. However, George and colleagues recently reported that 41 % of mostly male liver cirrhotics suffer from hypogonadism and 68 % from low bone mineral density [27]. These high prevalences of hypogonadism and low bone mineral density in liver cirrhotics make it very unlikely that hyperprolactinemia plays a significant role in pathophysiology of these disorders in advanced chronic liver disease. In former studies higher rates of hyperprolactinemia (12–14 %) have been reported in chronic liver disease [5, 18]. These discrepancies might at least partly result from methodological differences. Nowadays the use of the PEG precipitation method allows to distinguish between real hyperprolactinemia and macroprolactin in most cases [28, 29]. Given an estimated prevalence of macroprolactinemia of 10–25 % in patients with hyperprolactinemia and of 3.7 % in the general population [30], formerly reported high frequencies of hyperprolactinemia in patients with advanced chronic liver disease might partly be explained by lack of differentiation between real hyperprolactinemia and macroprolactinemia. In contrast to these previous studies, Seehofer et al. also reported normal prolactin levels in 22 patients with chronic hepatic failure before and after liver transplantation [12]. These data support our hypothesis that chronic hepatic failure is not a common cause of hyperprolactinemia. In patients with hyperprolactinemia, serum prolactin levels were only mildly elevated. In vitro ethanol was shown to affect prolactin levels by interfering with dopamine metabolism and modulating lactotropic cell proliferation [8] suggesting that these effects might contribute to the formerly reported increased rate of hyperprolactinemia in patients with liver cirrhosis. However, in our study serum prolactin levels were similar in patients with alcoholic liver disease and patients with non-alcoholic fatty liver disease, autoimmune disorders or viral hepatitis suggesting that chronic ethanol consumption has at least no irreversible or long term impact on prolactin synthesis in lactrotropic cells. While prolactin levels were similar in patients with cirrhosis of varying etiologies, serum prolactin levels significantly increased with progression of hepatic failure as estimated by the Child– Pugh Score. These results are partly in accordance with previous studies of Zietz et al. who reported increased prolactin levels in cirrhotics with Child–Pugh class C [6]. As shown by stepwise regression analysis ascites is a significant determinant of serum prolactin suggesting that the liver is critically involved in prolactin clearance. Accordingly, prolactin removal is impaired in states of portal hypertension. As expected, creatinine levels were another weak but significant determinant of serum prolactin levels underlining the role of the
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802 Endocrine Care
kidneys in prolactin clearance. Accordingly, hyperprolactinemia is found in about one-third of patients with chronic kidney disease [19, 31]. In summary, we found that in contrast to previous studies prevalence of hyperprolactinemia is unexpectedly low in patients with liver cirrhosis. Mild hyperprolactinemia is mostly found in patients who are taking drugs or have co-morbidities which are known as inducers of hyperprolactinemia. We thus conclude that liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that potentially increase prolactin levels marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.
Conflict of Interest
▼
The authors declare that they have no conflicts of interest in the authorship or publication of this contribution.
References 1 Klibanski A. Clinical practice. Prolactinomas. N Engl J Med 2010; 362: 1219–1226 2 Burra P. Liver abnormalities and endocrine diseases. Best Pract Res Clin Gastroenterol 2013; 27: 553–563 3 Ninkovic M, Love SA, Tom B, Alexander GJ, Compston JE. High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation. Calcif Tissue Int 2001; 69: 321–326 4 Compston JE. Osteoporosis after liver transplantation. Liver Transpl 2003; 9: 321–330 5 Morgan MY, Jakobovits AW, Gore MB, Wills MR, Sherlock S. Serum prolactin in liver disease and its relationship to gynaecomastia. Gut 1978; 19: 170–174 6 Zietz B, Lock G, Plach B, Drobnik W, Grossmann J, Scholmerich J, Straub RH. Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis. Eur J Gastroenterol Hepatol 2003; 15: 495–501 7 De A, Boyadjieva N, Pastorcic M, Sarkar D. Potentiation of the mitogenic effect of estrogen on the pituitary-gland by alcohol-consumption. Int J Oncol 1995; 7: 643–648 8 Sengupta A, Sarkar DK. Roles of dopamine 2 receptor isoforms and g proteins in ethanol regulated prolactin synthesis and lactotropic cell proliferation. PloS One 2012; 7: e45593 9 Murdoch FE, Byrne LM, Ariazi EA, Furlow JD, Meier DA, Gorski J. Estrogen receptor binding to DNA: affinity for nonpalindromic elements from the rat prolactin gene. Biochemistry 1995; 34: 9144–9150 10 Malayer JR, Gorski J. The role of estrogen receptor in modulation of chromatin conformation in the 5′ flanking region of the rat prolactin gene. Mol Cell Endocrinol 1995; 113: 145–154 11 Gordon GG, Olivo J, Rafil F, Southren AL. Conversion of androgens to estrogens in cirrhosis of the liver. J Clin Endocrinol Metab 1975; 40: 1018–1026 12 Seehofer D, Steinmueller T, Graef KJ, Rayes N, Wiegand W, Tullius SG, Settmacher U, Neuhaus P. Pituitary function test and endocrine status in patient with cirrhosis of the liver before and after hepatic transplantation. Ann Transplant 2002; 7: 32–37
13 Velissaris D, Karanikolas M, Kalogeropoulos A, Solomou E, Polychronopoulos P, Thomopoulos K, Labropoulou-Karatza C. Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy. World J Gastroenterol 2008; 14: 4190–4195 14 Sadideen H, Swaminathan R. Macroprolactin: what is it and what is its importance? Int J Clin Pract 2006; 60: 457–461 15 Madhusoodanan S, Parida S, Jimenez C. Hyperprolactinemia associated with psychotropics – a review. Hum Psychopharmacol 2010; 25: 281–297 16 Mertens B, Vanderheyden P, Michotte Y, Sarre S. Direct angiotensin II type 2 receptor stimulation decreases dopamine synthesis in the rat striatum. Neuropharmacology 2010; 58: 1038–1044 17 Mediskou P, Yavropoulou MP, Kotsa K, Tsekmekidou X, Psarakou-Gotzamani A, Papazisi A, Chlorou A, Yovos JG. The renin-angiotensin-aldosterone axis in patients with nontumoral [corrected] hyperprolactinemia. Clin Endocrinol 2011; 74: 306–311 18 Farthing MJ, Green JR, Edwards CR, Dawson AM. Progesterone, prolactin, and gynaecomastia in men with liver disease. Gut 1982; 23: 276–279 19 Chahal J, Schlechte J. Hyperprolactinemia. Pituitary 2008; 11: 141–146 20 Melmed S, Casanueva FF, Hoffman AR, Kleinberg DL, Montori VM, Schlechte JA, Wass JA, Endocrine S. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 273–288 21 Bernichtein S, Touraine P, Goffin V. New concepts in prolactin biology. J Endocrinol 2010; 206: 1–11 22 Ignacak A, Kasztelnik M, Sliwa T, Korbut RA, Rajda K, Guzik TJ. Prolactin–not only lactotrophin. A “new” view of the “old” hormone. J Physiol Pharmacol 2012; 63: 435–443 23 Olazabal IM, Munoz JA, Rodriguez-Navas C, Alvarez L, Delgado-Baeza E, Garcia-Ruiz JP. Prolactin’s role in the early stages of liver regeneration in rats. J Cell Physiol 2009; 219: 626–633 24 Kloehn S, Otte C, Korsanke M, Arendt T, Clemens A, Glasow A, Bornstein SR, Folsch UR, Monig H. Expression and distribution of the prolactin receptor in normal rat liver and in experimental liver cirrhosis. Horm Metab Res 2001; 33: 394–401 25 Simon-Holtorf J, Monig H, Klomp HJ, Reinecke-Luthge A, Folsch UR, Kloehn S. Expression and distribution of prolactin receptor in normal, fibrotic, and cirrhotic human liver. Exp Clin Endocrinol Diabetes 2006; 114: 584–589 26 Biller BM. Diagnostic evaluation of hyperprolactinemia. J Reprod Med 1999; 44: 1095–1099 27 George J, Ganesh HK, Acharya S, Bandgar TR, Shivane V, Karvat A, Bhatia SJ, Shah S, Menon PS, Shah N. Bone mineral density and disorders of mineral metabolism in chronic liver disease. World J Gastroenterol 2009; 15: 3516–3522 28 Fahie-Wilson MN, Soule SG. Macroprolactinaemia: contribution to hyperprolactinaemia in a district general hospital and evaluation of a screening test based on precipitation with polyethylene glycol. Ann Clin Biochem 1997; 34: 252–258 29 Olukoga AO, Kane JW. Macroprolactinaemia: validation and application of the polyethylene glycol precipitation test and clinical characterization of the condition. Clin Endocrinol 1999; 51: 119–126 30 Shimatsu A, Hattori N. Macroprolactinemia: diagnostic, clinical, and pathogenic significance. Clin Dev Immunol 2012; 2012: 167132 31 Lim VS, Kathpalia SC, Frohman LA. Hyperprolactinemia and impaired pituitary response to suppression and stimulation in chronic renal failure: reversal after transplantation. J Clin Endocrinol Metab 1979; 48: 101–107
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
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Endocrine Care 803
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Serum Prolactin in Advanced Chronic Liver Disease
Affiliations
Key words
▶ prolactin ● ▶ liver cirrhosis ● ▶ Child–Pugh score ●
C. Ress1, P.-A. Maeser1, A. Tschoner1, L. Loacker2, K. Salzmann1, G. Staudacher1, A. Melmer1, H. Zoller3, W. Vogel3, A. Griesmacher2, H. Tilg1, I. Graziadei3, 4, S. Kaser1 1
Department of Internal Medicine I, Medical University Innsbruck, Innsbruck, Austria Central Institute for Medical and Chemical Laboratory Diagnostics, Medical University Innsbruck, Innsbruck, Austria 3 Department of Internal Medicine II, Medical University Innsbruck, Innsbruck, Austria 4 Division of Internal Medicine, Hospital Hall in Tirol, Hall, Austria 2
Abstract
▼
Hyperprolactinemia is a frequent endocrine disorder with well known harmful effects on the reproductive system and bone metabolism. Besides prolactinomas several drugs and disorders such as renal failure and hypothyroidism have been shown to cause hyperprolactinemia. Based on former studies, liver cirrhosis has also been suggested to cause hyperprolactinemia, while mechanisms have not been identified yet. In this study, we set out to investigate the prevalence and predictors of hyperprolactinemia in 178 patients with liver cirrhosis of different etiologies. Eighteen out of 178 patients – 7 females and 11 males – displayed elevated serum prolactin levels. When patients were excluded who
Introduction received 25.01.2014 accepted 07.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375612 Published online: May 9, 2014 Horm Metab Res 2014; 46: 800–803 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence S. Kaser, MD Department of Internal Medicine I Medical University Innsbruck Anichstrasse 35 6020 Innsbruck Austria Tel.: + 43/512/504 81407 Fax: + 43/512/504 28539 [email protected]
▼
Hyperprolactinemia is a common endocrine disorder that is frequently associated with hypogonadism, infertility, and bone loss in the long term [1]. All these clinical entities are commonly found in liver cirrhotics [2]. As an example, osteoporosis and increased fracture risk have been shown to be a clinically relevant problem in liver transplant recipients, and osteoporosis is not only found after but even prior to liver transplantation [3, 4]. There are several physiological as well as also pathological conditions that cause hyperprolactinemia: physiologically, prolactin levels are elevated in pregnancy and during nursing. Apart from that, disorders such as pituitary tumors, primary hypothyreoidism, conditions of neurogenic stimulation such as chest wall injury, renal failure or hypophysitis might cause hyperprolactinemia as well. Additionally, intake of several medications including antipsychotics, antidepressants, metoclopramide, and other gastric motility agents as well as some antihypertensive
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
suffered from co-morbidities or took medication that are discussed to potentially interfere with prolactin metabolism, only 3 males displayed increased serum prolactin levels. Prolactin levels were similar in patients with liver cirrhosis of different etiologies. Our data suggest that hyperprolactinemia is not commonly found in patients with liver cirrhosis, but is mostly associated with intake of drugs or presence of comorbidites which are known to potentially cause hyperprolactinemia. We thus hypothesize that in contrast to former studies liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that are known to potentially increase prolactin levels, marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.
drugs are associated with mild to moderate hyperprolactinemia [1]. Chronic liver disease has also been suggested to cause hyperprolactinemia for a long time [1]. The idea goes back to 1978 when Morgan [5] found that prolactin levels were unexpectedly high in patients with chronic liver disease. Additionally, prolactin levels were shown to be elevated in cirrhotics with Child– Pugh Class C suggesting that hyperprolactinemia was correlated with stage of liver disease [6]. Mechanistically, direct and indirect effects of ethanol on lactotrophic cells and dopamine metabolism [7, 8] as well as increased estrogen levels have been suggested to contribute to hyperprolactinemia [9–11]. However, Zietz and colleagues found that prolactin levels were independent of etiology of liver disease [6, 12]. In contrast to the studies of Morgan et al. and Zietz et al., Seehofer and colleagues reported similar normal prolactin levels before and after transplantation [12]. Moreover Velissaris and colleagues [13] found no association between prolactin levels and severity of liver cirrhosis as estimated by the Child–Pugh Score.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
In this study, we set out to investigate prevalence and predictors of hyperprolactinemia in patients with liver cirrhosis.
Subjects and Methods
▼
Study population A cohort of 178 adult patients suffering from liver cirrhosis of different etiologies who were evaluated for liver transplantation between 2008 and 2011 at the University Hospital Innsbruck were included in the study. Etiologically, disorders were classified into chronic viral hepatitis, alcoholic or nonalcoholic fatty liver disease, autoimmune disorders, inherited metabolic liver diseases, and cryptogenic liver diseases. Patients with acute liver failure, patients who had undergone liver transplantation before as well as one patient with Morbus Cushing were excluded from the study. Additionally, patients with cholangiocarcinoma, mucoviscidosis, and polycystic liver disease were excluded from the study. At the time of investigation, all patients have been abstinent from alcohol for at least 6 months. The study was approved by the local ethics committee and all patients gave their informed written consent.
9.3 ng/ml, IQR (7.1–15.5), males: median: 8.7 ng/ml, IQR (6.35– 12.5), p = 0.02]. In total, 7 female and 11 male patients displayed elevated serum prolactin levels [females: median 41.6 ng/ml, IQR (38.4–79.0), males: median: 19.4 ng/ml, IQR (18.8–23.6)]. From these 18 patients, 6 patients had disorders and 3 were treated with drugs that are well known to potentially cause hyperprolactinemia: 4 patients suffered from advanced chronic kidney disease (stages III–V) and 2 from overt hypothyroidism (TSH > 4 mU/l), 1 patient received opiates for pain relief, 1 patient was under systemic glucocorticoid, and 1 under antidepressant therapy (serotonine reuptake inhibitor), respectively [1, 15]. Additionally, 6 patients received treatment with aldosterone antagonists. As the renin angiotensin system has been discussed to potentially affect dopamine and prolactin metabolism [16, 17], these patients were also considered to have a confounding factor that eventually influences prolactin levels. Accordingly, only 3 male patients with hyperprolactinemia had no disorder or received any treatment that potentially affects prolactin levels. Two patients with hyperprolactinemia without presence of confounding factors were classified as chronic liver disease of Child–Pugh class C and one of Child–Pugh class B.
Etiology of liver disease Laboratory measurements Blood samples were drawn after an overnight fast and rapidly processed or stored at − 80 °C after centrifugation. Liver function tests, renal function tests, thyroid-stimulating hormone levels, bilirubin, INR, and albumin levels were measured by commercially available kits. Serum prolactin levels were determined by a solid-phase 2 side chemoluminescent immunometric assay (Immulite 2000 Prolactin, Siemens). The presence of macropolactinemia was excluded by preparation of samples using the polyethylene glycol precipitation method [14]. Normal ranges were 1.9–25 ng/ml for adult females and 2.5–17 ng/ml for adult males.
▶ Table 1. To test whether Etiologies of liver disease are shown in ● etiology of liver disease affects serum prolactin levels, patients suffering from alcoholic liver disease (ALD) (n = 62), nonalcoholic steatohepatitis (NASH) (n = 32), viral hepatitis (n = 55), or autoimmune disorders (n = 25) were analyzed. Patients with cryptogenic liver disease (n = 3) or inherited metabolic liver disease (n = 1) were not included in this analysis. Serum prolactin levels were similar in all groups [ALD: median: 9.7 ng/ml, IQR (7.0–13.7), NAFLD: median: 7.8 ng/ml, IQR (6.0–10.5), viral hepatitis: median: 8.8 ng/ml, IQR (6.2–14.4), autoimmune disorders: median: 8.6 ng/ml, IQR (6.6–12.5), p = 0.45].
Stage of liver disease Statistical analysis Descriptive data are expressed as means ± SD. Statistical significance was inferred at a p-value of less than 0.05. The significance of differences in means between more than 2 groups was tested by ANOVA analysis with the Bonferroni correction. Shapiro-Wilk analysis was used to test for normality. Not normally distributed data were log-transformed in order to achieve normality for further analysis in which case data are presented as median and interquartile range (IQR) shown as range between the first and the third quartile except for male patients with hyperprolactinemia without confounding factors (median, min/max). Clinical characteristics are shown as means ± SD. A multiple stepwise linear regression analysis was done by entering the independent variable with the highest partial correlation coefficient at each step and a probability of F to enter ≤ 0.050 and a probability of F to remove ≥ 0.100. Statistical analysis was performed using the statistical software package for Windows Version 21 (SPSS, Chicago, IL, USA).
Results
▼
Prevalence of hyperprolactinemia Clinical characteristics of all study patients (n = 178) are shown ▶ Table 1. As expected, serum prolactin levels were signifiin ● cantly higher in female patients than in males [females: median:
Stage of liver disease was classified by the Child–Pugh Score. As ▶ Table 1, 35 patients were defined as Child–Pugh shown in ● class A, 98 patients as Child–Pugh class B, and 45 patients as Child–Pugh class C, respectively. Prolactin levels significantly increased with progression of liver disease as estimated by the ▶ Fig. 1); however, Child–Pugh score (classes A–C) (p < 0.01) (● Table 1 Clinical characteristics of study patients. Parameter (normal range) Age (years) Etiology of liver disease, n ALD NASH Viral hepatitis Autoimmune disorders Inherited metabolic liver disease Cryptogenic Creatinine, mg/dl (f: < 0.95, m: < 1.17) INR (PT), % (70–120) Albumin, g/l (41.9–53.5) Bilirubin, μmol/l ( < 22.1) Child–Pugh Score (A/B/C)
Females
Males
(n = 44)
(n = 134)
54.1 ± 11.0
58.2 ± 8.5
12 7 10 14 – 1 0.92 ± 0.38 1.49 ± 0.76 35.92 ± 6.91 89.90 ± 130.04 5/27/12
50 25 45 11 1 2 0.96 ± 0.48 1.53 ± 0.90 35.27 ± 6.22 81.40 ± 123.80 30/71/33
Values are means ± SD ALD: Alcoholic liver disease; NASH: Nonalcoholic steatohepatitis
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
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Fig. 1 Box- and whisker plot of serum prolactin levels for Child–Pugh classes groups. Serum prolactin levels significantly increased with class of chronic liver disease estimated by the Child–Pugh Score (p < 0.01). Median, IQR (box), ° outliers > 1 SD, * outliers > 2 SD.
significant differences in prolactin levels between the Child– Pugh classes were only found in males but not in females (data not shown).
Regression analysis When a multiple linear stepwise regression analysis including ascites, encephalopathy, albumin, bilirubin, and INR as independent variables was performed, ascites remained the only significant predictor of serum prolactin levels (R2: 0.054, β coefficient: 0.232, p < 0.01). When adding creatinine as an independent variable, ascites and creatinine were significant predictors of serum prolactin levels (F = 10.24, R2: 0.102; p = 0.02; ascites: β coefficient: 0.232, p < 0.01, creatinine: β coefficient: 0.217, p < 0.01).
Discussion
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Hyperprolactinemia is a prevalent endocrine disorder of varying etiology that has been shown to have long-term impact on bone health and sexual hormone metabolism. Decades ago it was reported that hyperprolactinemia is common in liver cirrhosis [5, 18]. As a result, liver cirrhosis is now a well-accepted etiology of hyperprolactinemia [19, 20]. While its effects on lactation und the reproductive function have widely been investigated, newer studies have also suggested tumor growth potency as well as several autocrine or paracrine actions by locally produced prolactin [21]. These different functions of prolactin are mediated by its receptor which is expressed in different tissues and cells such as lymphoid cells, endometrium, prostate and adipocytes [22]. Recently, prolactin was shown to accelerate liver regeneration in rodents [23]. In other studies it was shown that expression and distribution of prolactin receptors are different in cirrhotic, fibrotic, and healthy livers in both rodents and humans [24, 25]. Taken together these data suggest hepatic effects of prolactin, putting another complexion on hyperprolactinemia in advanced liver disease.
Ress C et al. Prolactin in Liver Cirrhosis … Horm Metab Res 2014; 46: 800–803
In our study, only 18 out of 178 patients had elevated serum prolactin levels. Thus, our data suggest that the prevalence of hyperprolactinemia in patients with advanced liver disease lies between the frequency reported in healthy adults (0.4 %) and the one in women with reproductive disorders (9–17 %) [26]. When excluding patients who took medications that are known to potentially cause hyperprolactinemia or who had co-morbidities that per se might be associated with hyperprolactinemia, only 3 out of 55 patients had hyperprolactinemia. We thus conclude from our findings that hyperprolactinemia in liver cirrhosis primarily results from associated diseases such as renal failure or is drug-induced while chronic liver disease itself seems not to be a common cause of hyperprolactinemia. The clinical relevance of mild hyperprolactinemia in these patients remains unclear. However, George and colleagues recently reported that 41 % of mostly male liver cirrhotics suffer from hypogonadism and 68 % from low bone mineral density [27]. These high prevalences of hypogonadism and low bone mineral density in liver cirrhotics make it very unlikely that hyperprolactinemia plays a significant role in pathophysiology of these disorders in advanced chronic liver disease. In former studies higher rates of hyperprolactinemia (12–14 %) have been reported in chronic liver disease [5, 18]. These discrepancies might at least partly result from methodological differences. Nowadays the use of the PEG precipitation method allows to distinguish between real hyperprolactinemia and macroprolactin in most cases [28, 29]. Given an estimated prevalence of macroprolactinemia of 10–25 % in patients with hyperprolactinemia and of 3.7 % in the general population [30], formerly reported high frequencies of hyperprolactinemia in patients with advanced chronic liver disease might partly be explained by lack of differentiation between real hyperprolactinemia and macroprolactinemia. In contrast to these previous studies, Seehofer et al. also reported normal prolactin levels in 22 patients with chronic hepatic failure before and after liver transplantation [12]. These data support our hypothesis that chronic hepatic failure is not a common cause of hyperprolactinemia. In patients with hyperprolactinemia, serum prolactin levels were only mildly elevated. In vitro ethanol was shown to affect prolactin levels by interfering with dopamine metabolism and modulating lactotropic cell proliferation [8] suggesting that these effects might contribute to the formerly reported increased rate of hyperprolactinemia in patients with liver cirrhosis. However, in our study serum prolactin levels were similar in patients with alcoholic liver disease and patients with non-alcoholic fatty liver disease, autoimmune disorders or viral hepatitis suggesting that chronic ethanol consumption has at least no irreversible or long term impact on prolactin synthesis in lactrotropic cells. While prolactin levels were similar in patients with cirrhosis of varying etiologies, serum prolactin levels significantly increased with progression of hepatic failure as estimated by the Child– Pugh Score. These results are partly in accordance with previous studies of Zietz et al. who reported increased prolactin levels in cirrhotics with Child–Pugh class C [6]. As shown by stepwise regression analysis ascites is a significant determinant of serum prolactin suggesting that the liver is critically involved in prolactin clearance. Accordingly, prolactin removal is impaired in states of portal hypertension. As expected, creatinine levels were another weak but significant determinant of serum prolactin levels underlining the role of the
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kidneys in prolactin clearance. Accordingly, hyperprolactinemia is found in about one-third of patients with chronic kidney disease [19, 31]. In summary, we found that in contrast to previous studies prevalence of hyperprolactinemia is unexpectedly low in patients with liver cirrhosis. Mild hyperprolactinemia is mostly found in patients who are taking drugs or have co-morbidities which are known as inducers of hyperprolactinemia. We thus conclude that liver cirrhosis is not a common cause of hyperprolactinemia and that in the absence of co-morbidities or drugs that potentially increase prolactin levels marked hyperprolactinemia needs further investigation in patients with liver cirrhosis.
Conflict of Interest
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The authors declare that they have no conflicts of interest in the authorship or publication of this contribution.
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