- Email: [email protected]
Liver abnormalities and endocrine diseases
Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Gastroenterology
7
Liver abnormalities and endocrine diseases Patrizia Burra, MD, PhD, Senior Lecturer * Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 PD Padua, Italy
a b s t r a c t Keywords: Addison’s disease Adrenocortical dysfunction Alcoholic liver disease Amenorrhoea Amiodarone Androgens Autoimmune diseases Cirrhosis Coagulation Cushing’s syndrome Diabetes Oestrogens Gonadal dysfunction Gonadotropin Growth hormone Hepatitis Hyperlipidaemia Hyperthyroidism Hypogonadism Hypothyroidism Insulin resistance Infertility Liver transplantation Non-alcoholic steatohepatitis Metabolic syndrome Obesity progesterone Propylthiouracil Sexual dysfunction Steatosis Thyrotoxicosis
The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex
* Tel.: þ39 049 821 8726; fax: þ39 049 821 8727. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.014
554
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Thyroid dysfucntion and the liver Thyroxine and tri-iodothyronine regulate the metabolic rate of hepatocytes and are essential for normal organ growth, development and function. Conversely, the liver is the site for thyroid hormone metabolism and plays a role in regulating their systemic effects. Consequently, thyroid dysfunction may alter liver function and liver disease may interfere with thyroid hormone metabolism. Moreover, various diseases including autoimmune and infiltrative disorders may affect both organs concomitantly [1]. Hypothyroidism and the liver Hypothyroidism may be associated with fatigue, myalgia, muscle cramps and elevated aspartate aminotransferase of muscular origin, reflecting an underlying myopathy [2]. Myxoedema ascites with a high protein concentration, proposed as a consequence of heart failure [3] or enhanced permeability of vascular endothelium [4], have both been reported in hypothyroidism. Liver histology is usually normal, and only rarely has fibrosis been described [5]. As far as biochemical alterations are concerned, abnormal liver function tests are commonly seen in primary thyroid disease. Cholestasis has been reported, and is possibly due to reduced bilirubin and bile excretion [6]. However, liver function tests generally return to normal with thyroxine replacement [7]. Hyperthyroidism and the liver Thyrotoxicosis may be associated with increased aspartate aminotransferase and alanine aminotransferase in nearly one third of patients due to hypoxia [8]. Likewise, increased alkaline phosphatase is reported in two third of patients and increased y-glutamyl transpeptidase in less than 20% of cases [9]. Histological evaluation in patients with thyrotoxicosis has revealed mild liver injury, with centrilobular cholestasis, and progression of liver damage is infrequent [10]. Furthermore, these abnormalities return to normal with the treatment of thyroid disease. A retrospective review of patients admitted to a single institution during ten years with acute thyrotoxicosis excluding iatrogenic causes, reported that 90.9% had Graves disease, 81.8% had some degree of hepatic abnormality, 63.6% had an elevation in one of both transaminases, and 18.2% had isolated synthetic dysfunction (elevated INT, decreased albumin) [11].
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
555
Anti-thyroid drugs and liver abnormalities Increased aspartate aminotransferase and alanine aminotransferase are observed in nearly one third of patients treated with propylthiouracil, and the rise is usually dose-related [12]. This constitutes an idiosyncratic reaction that can develop at any time [1] and is usually benign, despite cases of fulminant hepatic failure needing liver transplantation have been reported [13]. Drugs affecting the thyroid and the liver Amiodarone, the antimalarian drug mefloquine, the anti-epileptic drug carbamazepine, chemotherapy, and radiotherapy have all been associated with both thyroid and liver toxicity [1]. Thyroid disorders in liver diseases Patients with autoimmune hepatitis or primary biliary cirrhosis have a higher than expected incidence of thyroid dysfunction. As a matter of fact, hypothyroidism is a frequent finding in primary biliary cirrhosis [14,15]. From a series of patients with different aetiology of liver disease, the prevalence of thyroid dysfunction was reported to be 13% in primary biliary cirrhosis, 11% in primary sclerosing cholangitis, and 25% in non-alcoholic fatty liver disease. The incidence was 2.9 patients per 100 person-years in primary biliary cirrhosis, 2.1 patients per 100 person-years in primary sclerosing cholangitis and in 1.8 patients per 100 person-years in non-alcoholic fatty liver disease [16]. Similarly, a high prevalence of thyroid autoantibodies or thyroid dysfunction has also been documented in patients with chronic hepatitis C [17]. Alcoholic liver disease is commonly associated with abnormalities in circulating levels of thyroid hormones, including elevation of T4 and TBG with normal free T4 and TSH [18]. The relative importance of alcohol consumption and the severity of liver disease in the aetiology of these changes and their relationship to clinical abnormalities was analysed in 31 subjects with alcohol-induced liver disease. Patients were divided according to the severity of histological features, such as fatty changes, hepatitis and cirrhosis. Circulating concentrations of thyroid hormones and binding proteins were measured in all subjects, and changes related to histology and liver function tests, as well as clinical endocrine status were analysed. A reduction in circulating freeT3 was noted in subjects with alcoholic hepatitis and cirrhosis, in association with normal or reduced levels of TSH. The absence of abnormalities in subjects with sole fatty changes despite similar alcohol intake, and the observed correlation between fT3 and liver function tests, suggested that changes in fT3 reflect the severity of the underlying liver disease [19]. The possibility that alcohol regulates the expression of thyroid hormone receptor mRNA levels was explored in a model involving human hepatocyte primary culture. Cells were exposed to different concentrations of ethanol for 24 hours, and was found to have no effect on the steady-state levels of either T3 receptor alpha 1 or alpha 2 mRNAs. In contrast, cell exposure to T3 affected either one or both of these mRNA levels in a complex manner, showing that the model was capable of revealing responses to other stimuli. The hypermetabolic effects of long-term alcohol consumption in humans could therefore be due to causes other than direct effect of ethanol on the regulation of thyroid hormone receptors [20]. Another clinical entity, hepatocellular carcinoma (HCC), is associated with elevated levels of TBG due to increased synthesis and secretion of TBG by HCC cells [21]. Regarding hepatitis in general, serum T3 levels are extremely variable, ranging from decreased, normal or increased [22]. An interesting retrospective study was performed in 18 patients with liver cirrhosis, eight in class A, eight in class B, and two in class C of Child-Pugh, with primary or induced thyroxine-treated hypothyroidism. Liver function tests were compared between subjects with normal vs. increased levels of TSH. A significant improvement in alanine aminotransferase, alkaline phosphatase, albumin, bilirubin and INR was found in the increased TSH group. The authors of that study concluded that euthyroid patients with cirrhosis might benefit from a controlled hypothyroidism [23]. Thyrotoxic effects of drugs used to treat liver diseases Interferon used in the treatment of chronic hepatitis C may cause thyroid dysfunction, leading to the development of autoimmune thyroiditis or subacute thyroiditis. Hypothyroidism is seen more
556
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
frequently than hyperthyroidism following interferon therapy [24]. Moreover, hypothyroidism may develop in patients treated with sorafenib, a bi-aryl urea with tyrosine protein kinase inhibitor properties employed orally in HCC therapy and in patients treated with transarterial chemoembolization for HCC [25,26]. Henceforth, routine monitoring of thyroid function should be considered during interferon and sorafenib treatment. Diseases which concomitantly affect the thyroid and the liver Various conditions may involve both the liver and the thyroid, particularly infiltrating malingnancies such as non-Hodgkin’s lymphoma, or systemic diseases such as amyloidosis and haemochromatosis [1]. Adrenal dysfunction and the liver The relationship between the adrenal gland and the liver is complex, and the dysfunction of one of these organs tends to cause functional abnormalities in the other organ as well [27]. Adrenal insufficiency and the liver Addison’s disease is associated with mildly elevated aminotransferases which can exceed two to three times the upper limit [28]. The mechanisms behind this elevation are not clear, but may be related to changes in body weight; notably, transaminase values generally return to normal after appropriate glucocorticoid replacement therapy [27]. Adrenal excess and the liver Cushing’s syndrome is associated with features of metabolic syndrome, including liver steatosis and insulin resistance. Hypertension caused by the up-regulation of the renin–angiotensin system contributes to the development of non-alcoholic fatty liver disease [27]. Adrenocortical dysfunction in liver disease In patients with cirrhosis, adrenal insufficiency is reported during sepsis and septic shock, and is associated with increased mortality. Some studies have shown that adrenal insufficiency is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation for causes other than sepsis, such as bleeding and ascites, and in liver transplant recipients, immediately after surgery. The effect of corticosteroid therapy in critically ill patients with liver disease is still controversial. Serum total cortisol overestimates adrenal insufficiency in cirrhosis and free cortisol measurement may be useful. Finally, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented [29]. Importantly, however, it has been noted that patients who may have normal adrenal function on initial testing, subsequently progress to overt adrenal failure, and this has been termed the adrenal-exhaustion syndrome [30]. Therefore, possibly adrenal dysfunction in liver disease may have a separate pathogenesis to that observed in sepsis, and this field offers potential areas for further research into this condition [31]. Pseudo-Cushing’s syndrome has been described in patients with alcohol-induced liver disease. Many of the documented cases demonstrate abnormal liver function tests and a study was performed which evaluates whether abnormal hepatic 11beta-hydroxysteroid dehydrogenase (HSD) activity may play a role in the pathogenesis of the condition. In that study, fourteen patients with alcoholic liver disease and 14 patients with non-alcoholic liver disease showed marked deficiency of 11betaHSD compared to controls. In the non-alcoholic chronic liver disease group, daily cortisol production rate was reduced appropriately, and normal plasma cortisol and urinary free cortisol levels were maintained. However, in the alcoholic liver disease group, there was no concomitant fall in the cortisol production rate compared to the nonalcoholic liver disease group and to controls. The finding of glucocorticoid excess in patients with alcoholic liver disease may indicate that alcohol-induced pseudo-Cushing’s syndrome develops as a result of continuing oral cortisol secretion in the presence of impaired cortisol metabolism. The latter is mediated
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
557
by defective hepatic 11-beta HSD activity, while the former might be due to either an abnormal glucocorticoid feedback or to stimulation of cortisol secretion at the level of the hypothalamus/pituitary [32]. Sex hormones and the liver Oestrogens Hepatic disorders are associated with the use of oral contraceptives, despite the incidence is lower with the use of lower doses of oestrogen and progesterone in current available contraceptives [33]. It is well known that ostrogens can cause cholestasis and risk factors include genetic predisposition, the presence of cholestatic liver disease and concomitant cholestatic syndrome [34,35]. Oestrogens play a role in the pathogenesis of Budd Chiari syndrome in a number of patients with this condition, directly causing thrombosis of hepatic veins or contributing to an underlying prothrombotic state [27]. Hepatic peliosis may be a complication of oral contraceptives, and the lesions resolve with therapy withdrawal [36]. Finally, oral contraceptives have been associated with the risk of developing hepatic adenomas, focal nodular hyperplasia, and haemangiomas [27]. Androgens The risk of liver function tests abnormalities following the use of androgenic hormones is relevant. Elevated aminotransferase levels or cholestasis may be observed not infrequently, while adenomas and even hepatocellular carcinoma may develop, also within a structurally unaltered liver. In fact, a young man with androgen intake for several years has been recently diagnosed with hepatocellular carcinoma at our unit. Following partial resection, alcohol injection, and transarterial embolization, tumour recurrence within an year from the last locoregional procedure has now prompted evaluation for liver transplantation as curative treatment. Gonadal dysfunction in liver diseases The normal function of the hypothalamic–pituitary–gonadal axis is affected in liver disease. Cirrhosis in general may be associated with hypogonadism and signs of feminization, suggesting altered levels of sex hormones. Testicular atrophy, low testosterone levels, decreased libido, infertility, and gynaecomastia are often recognized in men with cirrhosis. In cirrhotic patients, the oestrogen/androgen ratio is usually increased [37]. In vitro studies on isolated Leydig cells, isolated perfused rat testes, and testicular homogenates have all demonstrated reduced testosterone synthesis and concentrations [38]. Alcoholic liver disease, in particular, is associated with a myriad of alterations linked to sex hormones. Clinical signs of hypogonadism are commonly more pronounced in patients with alcoholic liver disease, due to the direct inhibitory effects of alcohol upon testes. Alcoholic liver disease is associated with abnormalities in circulating levels of gonadal steroid hormones. Increasing circulating oestradiol and reduction in testosterone have been found in male patients with alcohol-related hepatic fatty changes, hepatitis and cirrhosis. These findings suggest that both a direct effect of alcohol as well as hepatic dysfunction determine changes in gonadal steroids in men [19]. Haemochromatosis, a genetic disease which defective gene product abnormally modulates the uptake of transferrin by cells, causing excessive iron accumulation and toxicity in the pituitary and the testes [39], normally causes chronic liver disease as well; half of haemochromatosis patients present hypogonadism with testicular atrophy [37]. Liver transplantation, a strategy that has proved to constitute a curative treatment for patients with end stage liver disease as well as acute liver failure, offers a different scenario related to hormone metabolism. Significantly higher levels of prolactin and sex hormone binding globulin have been ascertained in cirrhosis male patients when compared to liver transplant recipients. Furthermore, it has been shown that the percentage of patients with severe erectile dysfunction is significantly greater in patients with cirrhosis vs. transplanted patients, and that sexual dysfunction correlates with more advanced age [40]. Among women, alcohol abuse causes disturbances in the hormonal status and the reproductive performance. Chronic alcohol consumption is associated with hypogonadism, loss of secondary sexual
558
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
characteristics, amenorrhoea and early menopause, due to a reduction in oestrogen and gonadotrophin secretion [37]. Female patients with cirrhosis show significantly lower levels of total testosterone and higher levels of prolactin and delta-4-androstenedione in comparison with patients who have undergone liver transplantation [41]. Metabolic syndrome and the liver Metabolic syndrome, type II diabetes, obesity, and hyperlipidaemia are linked to non-alcoholic fatty liver disease (NAFLD). The metabolic syndrome is characterized by a cluster of metabolic abnormalities including truncal obesity, glucose intolerance, hypertension and dyslipidemia. The challenge endocrinologists face in the diagnosis of NAFLD is that signs and symptoms are frequently absent or nonspecific and can be easily missed. Frequently, these patients are characterized by obesity-related complications such as metabolic syndrome and type II diabetes. Liver fat accumulation may range from steatosis to severe steatohepatitis, with progression into fibrosis, cirrhosis, and a high risk of HCC. If elevated, liver aminotransferases may be helpful in making the diagnosis, but liver disease may exist in the presence of normal transaminases. Although liver ultrasound and MRI can aid the clinician, a liver biopsy is usually necessary to establish the diagnosis of NASH [42]. Insulin resistance is the most important metabolic abnormality of this syndrome and it seems to play a relevant role in the pathogenesis and progression of NAFLD [27]. In this regard, cytokines play a role in the development of insulin resistance. Leptin, for instance, is a cytokine produced by the adipose tissue and is involved in the regulation of food intake. In animal models, leptin deficiency causes metabolic and endocrine disorders including obesity, hypogonadism, hypothyroidism, insulin resistance, and diabetes [27]. Resistin, another cytokine, is a pro-inflammatory agent associated with insulin resistance in patients with type II diabetes. In patients with non-alcoholic steatohepatitis (NASH), high levels of resistin have been reported. Furthermore, the PPAR-activating thiazolidinedione rosiglitazone lowers resistin levels and resistin gene expression in animal models, and has been shown to improve liver function tests, but not fibrosis, in humans [43–45]. Irrespective of body mass index, the presence of type II diabetes increases the risk of NAFLD when compared with subjects with normal glucose levels or impaired glucose tolerance [46]. Type II diabetes may negatively affect the outcome of patients with liver disease, especially in patients with NAFLD, in whom metabolic syndrome increases the risk of cardiovascular diseases, type II diabetes, and NASH [47]. The incidence of NAFLD is increasing worldwide, and cirrhosis and hepatocellular carcinoma may become the leading indication for liver transplantation in the next future. In addition, the risk of developing metabolic syndrome after liver transplantation is well known. At the Multivisceral Transplant Unit of the Padua University Hospital, a study has determined the prevalence of type II diabetes and hypertension in 182 patients with at least five years of follow up after liver transplantation. Diabetes was found in 30% of cases and hypertension in 50% of cases, and were both significantly more frequent in male compared to female liver transplant recipients. Cardiovascular events, observed in 7% of cases, were more frequently seen in patients with features of metabolic syndrome (unpublished data). Growth hormone and metabolic syndrome The metabolic effects of growth hormone include hyperglycemia, hyperinsulineamia and lipolysis, and patients with excess of this hormone may develop features that resemble metabolic syndrome [37]. In patients with hypothalamic or pituitary disease obesity, impaired glucose tolerance, NAFLD, NASH, and cirrhosis have been described [48]. The liver is the major source of circulating insulin-like growth factor-1 (IFG-1) and has been suggested as a major source of at least two of the major binding proteins that modify bioavailability [49]. Growing evidence has revealed that GH as well as IGF-I play an essential role in the liver. Further research is needed to define the mechanisms by which GH and IGF-I exert their effects in the liver [50]. In this regard, IGF-1 levels were demonstrated to correlate with differences in fibrosis in 55 patients with NAFLD: on multivariate analysis, platelet count and IGF-1 showed a significant association with stage 2–3 NAFLD. Although there was no relationship of fibrosis with GH level, decreased GH was significantly associated with stage 2–3 steatosis, while a low
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
559
GH/IGF-1 ratio was found in advanced steatosis. The authors of this study concluded that GH and IGF-1 are associated with hepatic fibrosis and steatosis in NAFLD [51]. Ovarian dysfunction and metabolic syndrome Polycystic ovary syndrome is the most common endocrine abnormality in premenopausal women, and the prevalence of insulin resistance and hyperinsulinaemia is increased in such patients. Clinical features are the result of increased testosterone secretion by ovaries that are generally normally insulin-sensitive, secondary to the higher circulating insulin concentrations. Nevertheless, not all insulin-resistant women have polycystic ovary syndrome and viceversa [52]. Haemostatic abnormalities in endocrine and liver disorders The haemostatic balance is a complex system regulated by several factors, including hormones. There is strong evidence that abnormalities of coagulation and fibrinolysis can be seen in patients with endocrine disorders including hypothyroidism, hyperthyroidism, Cushing’s syndrome, GH-related pituitary dysfunctions, pituitary prolactine-producing adenomas, polycystic ovary syndrome, and primary hyperparathyroidism. Similarly, metabolic syndrome is associated with enhanced coagulation and impaired fibrinolysis. Overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine disorders in general are associated with an elevation in the risk of thrombosis. There is a general consensus that patients with Cushing’ syndrome are at high risk of venous thromboembolism, and prophylaxis with low-molecular-weight heparin should be considered in these cases. Bleeding in overt hypothyroidism can be related to an acquired von Willebrand’s disease type I. Except for metabolic syndrome, however, the number of studies that have been performed analysing haemostasis disorders in patients with endocrine diseases is limited and the number of patients studied is small [53]. Patients with metabolic syndrome are at increased risk of cardiovascular diseases [54], and the syndrome is frequently associated with a prothrombotic state, characterized by increased plasmatic coagulation, reduced fibrinolysis, decreased endothelial thrombo-resistance and platelet hyperactivity, contributing to the development of cardiovascular complications [55,56]. Low-dose aspirin prophylaxis is usually recommended in patients affected by metabolic syndrome, but there are no specific studies of the use of aspirin or anti-platelet agents for the primary prevention of cardiovascular events in these patients [54–56]. Nonetheless, the prophylactic use of low-dose aspirin in the prevention of cardiovascular disease in patients with metabolic syndrome, but without diabetes, as well as in those with endocrine disorders should be considered based on clinical judgement [53]. Statins and the liver Several studies have confirmed that lipid-lowering therapy reduces the risk of cardiovascular events [57], and statins are commonly used for primary and secondary prevention of myocardial infarction, owing to their positive effect on the lipid profile together with their general safety and tolerability, which has been established in thousands of treated patients [58]. Serious adverse events, however, have been reported including myopathy, rhabdomyolisis and elevated transaminase levels, and liver function tests should therefore be monitored before and regularly after starting statin therapy. There is some data however, reporting that abnormalities of liver function tests may be the consequence of statin’s lipid-lowering effect rather than true toxicity to the liver [59,60]. A meta-analysis of randomized controlled trials of statins used for the treatment of hyperlipidaemia or for primary or secondary prevention of cardiovascular disease published nearly ten years ago demonstrated that the proportion of patients with abnormal liver function tests was low (1.14%) in patients taking statins, vs. 1.05% in placebo-treated patients (OR 1.26, 95% CI 0.99–1.62, p ¼ 0.07). Only fluvastatin was associated with a significant increased in the odds of having liver function test abnormalities (fluvastatin 1.13% vs. placebo 0.29%, OR 3.54, 95% CI 1.1–11.6, p ¼ 0.04). The authors concluded that pravastatin, lovastatin, and simvastatin at low-to-moderate doses were not associated with a significant risk of liver function test abnormalities [58]. Moreover, coexisting transaminase elevation in non-alcoholic fatty liver disease and stable hepatitis C and B viral infections is not a contraindication to statin use [61].
560
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
Oral hypoglycemic agents and the liver Type II diabetes is often associated with metabolic syndrome, and overt diabetes mellitus is present in 21–40% of patients with cirrhosis. The prevalence of glucose metabolism disorders was reported to be 79% in a small group of patients with cirrhosis, of whom 19% had type II diabetes. Overall, glucose metabolism disorders were subclinical in 415 of cases [62]. Metformin, an insulin sensitizer which decreases insulin secretion and ameliorates the hyperinsulinaemic status, has been studied extensively studied in diverse scenarios. An interesting study was performed on 82 patients with liver cirrhosis and type II diabetes, 41 of whom were on metformin and 41 without metformin treatment. Metformin was found to be independently related to overt hepatic encephalopathy in patients with type II diabetes and high risk of encephalopathy, while it was shown to inhibit glutaminase activity in vitro, which could theoretically be protective against encephalopathy in the same study [63]. From a large series of 44.406 patients with type II diabetes exposed to oral antidiabetic agents, 605 were identified as having liver disease, and of this subgroup, 186 had non-symptomatic, mild, and transient liver disorders, 249 had a predisposing condition, and 113 had another cause of liver disease. A total of 57 cases were possibly drug-induced, with an incidence rate of 5/10.000 personyears (3.9–6.5). Of these, 11 cases were attributed to other drugs and eight were attributed to fatty liver disease of diabetes. Oral antidiabetic agents were continued in 51 of these 57 cases. In conclusion in this large population of patients with type II diabetes treated with oral antidiabetic agents, the incidence of liver disease was high, but most cases involved other diseases that may cause liver disease [64]. Conclusions Being the liver involved in such a myriad of metabolic processes, it is clearly a key component that has both an impact on the endocrine system, as well as being an inevitable target during the course of endocrine disorders or the treatments they require. Not only infrequent disorders such as haemochromatosis and infiltrative malignancies are able to cause hepatic and endocrine derangements, but present-day epidemic diseases such as metabolic syndrome impose the need for the integration between the two fields both in terms of diagnosis as well as therapy. Clearly, it is ever more important to be prepared to deal with multiple drug interactions, and the effects of obesity and insulin resistance, in a worldwide population that tends to be aged and have numerous comorbidities.
Practice points: The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. An unabridged list of pharmacological agents, including not only prescription medication but also herbal preparations and over-the-counter drugs, must be a fundamental component of the initial evaluation of hepatic disorders in the presence of endocrine abnormalities. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases, as well as therapeutic agents used to treat these endocrine disorders must be excluded in transaminase elevation of unknown cause. Adrenal insufficiency should be promptly identified and treated in decompensated cirrhosis patients, especially during episodes of sepsis, as this complication increases mortality. In cases of alcohol abuse and endocrine abnormalities such as feminization in men, sex hormone panel must be firstly evaluated, but special attention should be drawn to excluding an underlying liver disease. Patients with metabolic syndrome, the pandemia of the present and future centuries, must be evaluated diligently in terms of liver damage, in order to exclude steatosis, fibrosis, cirrhosis and hepatocellular carcinoma.
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
561
Research agenda: Although direct gonadal inhibitory effects of alcohol have been widely demonstrated in the mouse animal model, further studies are needed to clarify the role of this agent vs. the importance of liver damage induced by alcohol. In the era of increasing number of patients being transplanted because of non-alcoholic steatohepatitis (NASH) leading to cirrhosis and hepatocellular carcinoma (HCC), and given the high incidence of post-transplant metabolic syndrome, future studies will be needed to establish strategies to avoid graft loss, increased cardiovascular risk post-transplant, and to eventually re-evaluate allocation criteria. Studies on decompensation in cirrhosis patients, especially during episodes of sepsis, will further characterize adrenal insufficiency in these patients and will provide clinicians with new therapeutic protocols to apply in these circumstances.
Conflict of interest statement No conflict of interest.
Acknowledgements Dr. Giacomo Germani, MD, PhD and Dr. Kryssia Rodríguez-Castro, MD, PhD.
References [1] Malik R, Hodgson H. The relationship between the thyroid gland and the liver. QJM 2002;95:559–69. [2] Laycock MA, Pascuzzi RM. The neuromuscular effects of hypothyroidism. Semin Neurol 1991;11:288–94. [3] Kinney EL, Wright RJ, Caldwell JW. Value of clinical features for distinguishing myxedema ascites from other forms of ascites. Comput Biol Med 1989;19:55–9. [4] Baker A, Kaplan M, Wolfe H. Central congestive fibrosis of the liver in myxedema ascites. Ann Intern Med 1972;77:927–9. [5] Klein I, Levey GS. Unusual manifestations of hypothyroidism. Arch Intern Med 1984;144:123–8. [6] Van Steenbergen W, Fevery J, De Vos R, Leyten R, Heirwegh KP, De Groote J. Thyroid hormones and the hepatic handling of bilirubin. I. Effects of hypothyroidism and hyperthyroidism on the hepatic transport of bilirubin mono- and diconjugates in the Wistar rat. Hepatology 1989;9:314–21. [7] Gaitan E, Cooper DS. Primary hypothyroidism. Curr Ther Endocrinol Metab 1997;6:94–8. [8] Thompson Jr P, Strum D, Boehm T, Wartofsky L. Abnormalities of liver function tests in tyrotoxicosis. Mil Med 1978;143: 548–51. [9] Doran GR. Serum enzyme disturbances in thyrotoxicosis and myxoedema. J R Soc Med 1978;71:189–94. [10] Sola J, Pardo-Mindán FJ, Zozaya J, Quiroga J, Sangro B, Prieto J. Liver changes in patients with hyperthyroidism. Liver 1991; 11:193–7. [11] Elias R, Dean DS, Barsness GW. Hepatic dysfunction in hospitalized patients with acute thyrotoxicosis: a decade of experience. Endocrinology 2012:1–6. [12] Williams KV, Nayak S, Becker D, Reyes J, Burmeister LA. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 1997;82:1727–33. [13] Levy M. Propylthiouracil hepatotoxicity. A review and case presentation. Clin Pediatr (Phila) 1993;32:25–9. [14] Golding PL, Smith M, Williams R. Multisystem involvement in chronic liver disease. Studies on the incidence and pathogenesis. Am J Med 1973;55:772–82. [15] Elta GH, Sepersky RA, Goldberg MJ, Connors CM, Miller KB, Kaplan MM. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983;28:971–5. [16] Silveira MG, Mendes FD, Diehl NN, Enders FT, Lindor KD. Thyroid dysfunction in primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease. Liver Int 2009;29:1094–100. [17] Pateron D, Hartmann DJ, Duclos-Vallee JC, Jouanolle H, Beaugrand M. Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 1993;17:417–9. [18] Huang MJ, Liaw YF. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 1995;10:344–50. [19] Burra P, Franklyn JA, Ramsden DB, Elias E, Sheppard MC. Severity of alcoholic liver disease and markers of thyroid and steroid status. Postgrad Med J 1992;68:804–10. [20] Burra P, Fitch NJ, Kapadi A, Franklyn JA, Sheppard MC, Ramsden DB, et al. The effects of ethanol, 3,5,30 -triiodothyronine (T3) and oestradiol (E2) on thyroid hormone nuclear receptor expression in human hepatocyte primary cultures. Alcohol Alcohol 1995;30:219–21.
562
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
[21] Huang MJ, Liaw YF. Thyroxine-binding globulin in patients with chronic hepatitis B virus infection: different implications in hepatitis and hepatocellular carcinoma. Am J Gastroenterol 1990;85:281–4. [22] L’Age M, Meinhold H, Wenzel KW, Schleusener H. Relations between serum levels of TSH, TBG, T4, T3, rT3 and various histologically classified chronic liver diseases. J Endocrinol Invest 1980;3:379–83. [23] Oren R, Sikuler E, Wong F, Blendis LM, Halpern Z. The effects of hypothyroidism on liver status of cirrhotic patients. J Clin Gastroenterol 2000;31:162–3. [24] Koh LK, Greenspan FS, Yeo PP. Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 1997;7:891–6. [25] Flohr F, Harder J, Seufert J, Blum HE, Spangenberg HC. Hypothyroidism in patients with hepatocellular carcinoma treated by transarterial chemoembolization. Hepatology 2008;47:2144. [26] Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, Dreicer R, et al. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 2008;19:265–8. [27] Maheshwari A, Thuluvath PJ. Endocrine diseases and the liver. Clin Liver Dis 2011;15:55–67. [28] Boulton R, Hamilton MI, Dhillon AP, Kinloch JD, Burroughs AK. Subclinical Addison’s disease: a cause of persistent abnormalities in transaminase values. Gastroenterology 1995;109:1324–7. [29] Fede G, Spadaro L, Tomaselli T, Privitera G, Germani G, Tsochatzis E, et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 2012;55:1282–91. [30] Marik PE. Adrenal-exhaustion syndrome in patients with liver disease. Intensive Care Med 2006;32:275–80. [31] O’Beirne J, Holmes M, Agarwal B, Bouloux P, Shaw S, Patch D, et al. Adrenal insufficiency in liver disease – what is the evidence? J Hepatol 2007;47:418–23. [32] Stewart PM, Burra P, Shackleton CH, Sheppard MC, Elias E. 11 Beta-hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease. J Clin Endocrinol Metab 1993;76:748–51. [33] Lindgren A, Olsson R. Liver damage from low-dose oral contraceptives. J Intern Med 1993;234:287–92. [34] Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8–23. [35] Reyes H, Gonzalez MC, Ribalta J, Aburto H, Matus C, Schramm G, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978;88:487–93. [36] Weinberger M, Garty M, Cohen M, Russo Y, Rosenfeld JB. Ultrasonography in the diagnosis and follow-up of hepatic sinusoidal dilatation. Arch Intern Med 1985;145:927–9. [37] Karagiannis A, Harsoulis F. Gonadal dysfunction in systemic diseases. Eur J Endocrinol 2005;152:501–13. [38] De Maria N, Colantoni A, Van Thied D. The liver and endoscrine function. In: Becker KL, Bilezikian John P, Bremner William J, editors. Principles and practice of endocrinology and metabolism. Wilkins; 2000. p. 1870–85. [39] Cox TM, Kelly AL. Haemochromatosis: an inherited metal and toxicity syndrome. Curr Opin Genet Dev 1998;8:274–81. [40] Burra P. Sexual dysfunction after liver transplantation. Liver Transpl 2009;(15 Suppl. 2):S50–6. [41] Burra P, Germani G, Masier A, De Martin E, Gambato M, Salonia A. Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure? Transplantation 2010;89:1425–9. [42] Lomonaco R, Chen J, Cusi K. An endocrine perspective of nonalcoholic fatty liver disease (NAFLD). Ther Adv Endocrinol Metab 2011;2:211–25. [43] Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 2006;91:1081–6. [44] Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51:445–53. [45] Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–12. [46] Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005;22:1141–5. [47] Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–23. [48] Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 2004;39:909–14. [49] Donaghy A, Ross R, Gimson A, Hughes SC, Holly J, Williams R. Growth hormone, insulinlike growth factor-1, and insulin like growth factor binding proteins 1 and 3 in chronic liver disease. Hepatology 1995;21:680–8. [50] Takahashi Y. Essential roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the liver. Endocr J 2012;59: 955–62. [51] Ichikawa T, Nakao K, Hamasaki K, Furukawa R, Tsuruta S, Ueda Y, et al. Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease. Hepatol Int 2007;1: 287–94. [52] Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 2003;14:365–70. [53] Franchini M, Lippi G, Manzato F, Vescovi PP, Targher G. Hemostatic abnormalities in endocrine and metabolic disorders. Eur J Endocrinol 2010;162:439–51. [54] Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocr Rev 2008; 29:777–822. [55] Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008;99:995–1000. [56] Mina A, Favaloro EJ, Koutts J. Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review. Semin Thromb Hemost 2007;33:798–809. [57] Stamler J, Wentworth D, Neaton JD. Prevalence and prognostic significance of hypercholesterolemia in men with hypertension. Prospective data on the primary screenees of the Multiple Risk Factor Intervention Trial. Am J Med 1986;80: 33–9. [58] de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 2004;24: 584–91.
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
563
[59] Roberts WC. Getting more people on statins. Am J Cardiol 2002;90:683–5. [60] Tolman KG. The liver and lovastatin. Am J Cardiol 2002;89:1374–80. [61] Gillett Jr RC, Norrell A. Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicity. Am Fam Physician 2011;83:711–6. [62] García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ, Reyes-Cabello E, González-González JA, Muñoz-Espinosa LE, et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012;11:240–8. [63] Ampuero J, Ranchal I, Nuñez D, Díaz-Herrero Mdel M, Maraver M, del Campo JA, et al. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279. [64] Jick SS, Stender M, Myers MW. Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents. Diabetes Care 1999;22:2067–71.
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Gastroenterology
7
Liver abnormalities and endocrine diseases Patrizia Burra, MD, PhD, Senior Lecturer * Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Via Giustiniani 2, 35128 PD Padua, Italy
a b s t r a c t Keywords: Addison’s disease Adrenocortical dysfunction Alcoholic liver disease Amenorrhoea Amiodarone Androgens Autoimmune diseases Cirrhosis Coagulation Cushing’s syndrome Diabetes Oestrogens Gonadal dysfunction Gonadotropin Growth hormone Hepatitis Hyperlipidaemia Hyperthyroidism Hypogonadism Hypothyroidism Insulin resistance Infertility Liver transplantation Non-alcoholic steatohepatitis Metabolic syndrome Obesity progesterone Propylthiouracil Sexual dysfunction Steatosis Thyrotoxicosis
The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases must be excluded in transaminase elevation of unknown cause. Drugs such as propylthiouracil, used in the treatment of hyperthyroidism, may induce liver damage, and other drugs such as amiodarone, carbamazepine, and several chemotherapeutic agents can lead to both thyroid and liver abnormalities. Liver diseases such as hepatitis, hepatocellular carcinoma, and cirrhosis may cause altered levels of thyroid hormones, and alcoholic liver disease, both due to the noxious substance ethanol as well as to the hepatic damage it causes, may be responsible for altered thyroid function. Both excess and insufficiency of adrenal function may result in altered liver function, and adrenocortical dysfunction may be present in patients with cirrhosis, especially during episodes of decompensation. Again an important player which affects both the endocrine system and the liver, alcohol may be associated with pseudo-Cushing syndrome. Sex hormones, both intrinsic as well as extrinsically administered, have an important impact on liver function. While oestrogens are related to cholestatic liver damage, androgens are the culprit of adenomas and hepatocellular carcinoma, among others. Chronic liver disease, on the other hand, has profound repercussions on sex
* Tel.: þ39 049 821 8726; fax: þ39 049 821 8727. E-mail address: [email protected]. 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.06.014
554
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
hormone metabolism, inducing feminization in men and infertility and amenorrhoea in women. Lastly, metabolic syndrome, the pandemia of the present and future centuries, links the spectrum of liver damage ranging from steatosis to cirrhosis, to the array of endocrine alterations that are features of the syndrome, including insulin resistance, central obesity, and hyperlipidaemia. Clinical practice must integrally evaluate the effects of the intricate and tight relationship between the liver and the endocrine system, in order to better address all manifestations, complications, and prevent deterioration of one or the other organ-system. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. The numerous and constant relationships and feedback mechanisms between the liver and all endocrine organs is reflected by the fact that an alteration of one oftentimes results in the malfunction of the other. Thyroid dysfucntion and the liver Thyroxine and tri-iodothyronine regulate the metabolic rate of hepatocytes and are essential for normal organ growth, development and function. Conversely, the liver is the site for thyroid hormone metabolism and plays a role in regulating their systemic effects. Consequently, thyroid dysfunction may alter liver function and liver disease may interfere with thyroid hormone metabolism. Moreover, various diseases including autoimmune and infiltrative disorders may affect both organs concomitantly [1]. Hypothyroidism and the liver Hypothyroidism may be associated with fatigue, myalgia, muscle cramps and elevated aspartate aminotransferase of muscular origin, reflecting an underlying myopathy [2]. Myxoedema ascites with a high protein concentration, proposed as a consequence of heart failure [3] or enhanced permeability of vascular endothelium [4], have both been reported in hypothyroidism. Liver histology is usually normal, and only rarely has fibrosis been described [5]. As far as biochemical alterations are concerned, abnormal liver function tests are commonly seen in primary thyroid disease. Cholestasis has been reported, and is possibly due to reduced bilirubin and bile excretion [6]. However, liver function tests generally return to normal with thyroxine replacement [7]. Hyperthyroidism and the liver Thyrotoxicosis may be associated with increased aspartate aminotransferase and alanine aminotransferase in nearly one third of patients due to hypoxia [8]. Likewise, increased alkaline phosphatase is reported in two third of patients and increased y-glutamyl transpeptidase in less than 20% of cases [9]. Histological evaluation in patients with thyrotoxicosis has revealed mild liver injury, with centrilobular cholestasis, and progression of liver damage is infrequent [10]. Furthermore, these abnormalities return to normal with the treatment of thyroid disease. A retrospective review of patients admitted to a single institution during ten years with acute thyrotoxicosis excluding iatrogenic causes, reported that 90.9% had Graves disease, 81.8% had some degree of hepatic abnormality, 63.6% had an elevation in one of both transaminases, and 18.2% had isolated synthetic dysfunction (elevated INT, decreased albumin) [11].
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
555
Anti-thyroid drugs and liver abnormalities Increased aspartate aminotransferase and alanine aminotransferase are observed in nearly one third of patients treated with propylthiouracil, and the rise is usually dose-related [12]. This constitutes an idiosyncratic reaction that can develop at any time [1] and is usually benign, despite cases of fulminant hepatic failure needing liver transplantation have been reported [13]. Drugs affecting the thyroid and the liver Amiodarone, the antimalarian drug mefloquine, the anti-epileptic drug carbamazepine, chemotherapy, and radiotherapy have all been associated with both thyroid and liver toxicity [1]. Thyroid disorders in liver diseases Patients with autoimmune hepatitis or primary biliary cirrhosis have a higher than expected incidence of thyroid dysfunction. As a matter of fact, hypothyroidism is a frequent finding in primary biliary cirrhosis [14,15]. From a series of patients with different aetiology of liver disease, the prevalence of thyroid dysfunction was reported to be 13% in primary biliary cirrhosis, 11% in primary sclerosing cholangitis, and 25% in non-alcoholic fatty liver disease. The incidence was 2.9 patients per 100 person-years in primary biliary cirrhosis, 2.1 patients per 100 person-years in primary sclerosing cholangitis and in 1.8 patients per 100 person-years in non-alcoholic fatty liver disease [16]. Similarly, a high prevalence of thyroid autoantibodies or thyroid dysfunction has also been documented in patients with chronic hepatitis C [17]. Alcoholic liver disease is commonly associated with abnormalities in circulating levels of thyroid hormones, including elevation of T4 and TBG with normal free T4 and TSH [18]. The relative importance of alcohol consumption and the severity of liver disease in the aetiology of these changes and their relationship to clinical abnormalities was analysed in 31 subjects with alcohol-induced liver disease. Patients were divided according to the severity of histological features, such as fatty changes, hepatitis and cirrhosis. Circulating concentrations of thyroid hormones and binding proteins were measured in all subjects, and changes related to histology and liver function tests, as well as clinical endocrine status were analysed. A reduction in circulating freeT3 was noted in subjects with alcoholic hepatitis and cirrhosis, in association with normal or reduced levels of TSH. The absence of abnormalities in subjects with sole fatty changes despite similar alcohol intake, and the observed correlation between fT3 and liver function tests, suggested that changes in fT3 reflect the severity of the underlying liver disease [19]. The possibility that alcohol regulates the expression of thyroid hormone receptor mRNA levels was explored in a model involving human hepatocyte primary culture. Cells were exposed to different concentrations of ethanol for 24 hours, and was found to have no effect on the steady-state levels of either T3 receptor alpha 1 or alpha 2 mRNAs. In contrast, cell exposure to T3 affected either one or both of these mRNA levels in a complex manner, showing that the model was capable of revealing responses to other stimuli. The hypermetabolic effects of long-term alcohol consumption in humans could therefore be due to causes other than direct effect of ethanol on the regulation of thyroid hormone receptors [20]. Another clinical entity, hepatocellular carcinoma (HCC), is associated with elevated levels of TBG due to increased synthesis and secretion of TBG by HCC cells [21]. Regarding hepatitis in general, serum T3 levels are extremely variable, ranging from decreased, normal or increased [22]. An interesting retrospective study was performed in 18 patients with liver cirrhosis, eight in class A, eight in class B, and two in class C of Child-Pugh, with primary or induced thyroxine-treated hypothyroidism. Liver function tests were compared between subjects with normal vs. increased levels of TSH. A significant improvement in alanine aminotransferase, alkaline phosphatase, albumin, bilirubin and INR was found in the increased TSH group. The authors of that study concluded that euthyroid patients with cirrhosis might benefit from a controlled hypothyroidism [23]. Thyrotoxic effects of drugs used to treat liver diseases Interferon used in the treatment of chronic hepatitis C may cause thyroid dysfunction, leading to the development of autoimmune thyroiditis or subacute thyroiditis. Hypothyroidism is seen more
556
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
frequently than hyperthyroidism following interferon therapy [24]. Moreover, hypothyroidism may develop in patients treated with sorafenib, a bi-aryl urea with tyrosine protein kinase inhibitor properties employed orally in HCC therapy and in patients treated with transarterial chemoembolization for HCC [25,26]. Henceforth, routine monitoring of thyroid function should be considered during interferon and sorafenib treatment. Diseases which concomitantly affect the thyroid and the liver Various conditions may involve both the liver and the thyroid, particularly infiltrating malingnancies such as non-Hodgkin’s lymphoma, or systemic diseases such as amyloidosis and haemochromatosis [1]. Adrenal dysfunction and the liver The relationship between the adrenal gland and the liver is complex, and the dysfunction of one of these organs tends to cause functional abnormalities in the other organ as well [27]. Adrenal insufficiency and the liver Addison’s disease is associated with mildly elevated aminotransferases which can exceed two to three times the upper limit [28]. The mechanisms behind this elevation are not clear, but may be related to changes in body weight; notably, transaminase values generally return to normal after appropriate glucocorticoid replacement therapy [27]. Adrenal excess and the liver Cushing’s syndrome is associated with features of metabolic syndrome, including liver steatosis and insulin resistance. Hypertension caused by the up-regulation of the renin–angiotensin system contributes to the development of non-alcoholic fatty liver disease [27]. Adrenocortical dysfunction in liver disease In patients with cirrhosis, adrenal insufficiency is reported during sepsis and septic shock, and is associated with increased mortality. Some studies have shown that adrenal insufficiency is frequent in stable cirrhosis as well as in cirrhosis associated with decompensation for causes other than sepsis, such as bleeding and ascites, and in liver transplant recipients, immediately after surgery. The effect of corticosteroid therapy in critically ill patients with liver disease is still controversial. Serum total cortisol overestimates adrenal insufficiency in cirrhosis and free cortisol measurement may be useful. Finally, the mechanisms by which liver disease leads to adrenal dysfunction are not sufficiently documented [29]. Importantly, however, it has been noted that patients who may have normal adrenal function on initial testing, subsequently progress to overt adrenal failure, and this has been termed the adrenal-exhaustion syndrome [30]. Therefore, possibly adrenal dysfunction in liver disease may have a separate pathogenesis to that observed in sepsis, and this field offers potential areas for further research into this condition [31]. Pseudo-Cushing’s syndrome has been described in patients with alcohol-induced liver disease. Many of the documented cases demonstrate abnormal liver function tests and a study was performed which evaluates whether abnormal hepatic 11beta-hydroxysteroid dehydrogenase (HSD) activity may play a role in the pathogenesis of the condition. In that study, fourteen patients with alcoholic liver disease and 14 patients with non-alcoholic liver disease showed marked deficiency of 11betaHSD compared to controls. In the non-alcoholic chronic liver disease group, daily cortisol production rate was reduced appropriately, and normal plasma cortisol and urinary free cortisol levels were maintained. However, in the alcoholic liver disease group, there was no concomitant fall in the cortisol production rate compared to the nonalcoholic liver disease group and to controls. The finding of glucocorticoid excess in patients with alcoholic liver disease may indicate that alcohol-induced pseudo-Cushing’s syndrome develops as a result of continuing oral cortisol secretion in the presence of impaired cortisol metabolism. The latter is mediated
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
557
by defective hepatic 11-beta HSD activity, while the former might be due to either an abnormal glucocorticoid feedback or to stimulation of cortisol secretion at the level of the hypothalamus/pituitary [32]. Sex hormones and the liver Oestrogens Hepatic disorders are associated with the use of oral contraceptives, despite the incidence is lower with the use of lower doses of oestrogen and progesterone in current available contraceptives [33]. It is well known that ostrogens can cause cholestasis and risk factors include genetic predisposition, the presence of cholestatic liver disease and concomitant cholestatic syndrome [34,35]. Oestrogens play a role in the pathogenesis of Budd Chiari syndrome in a number of patients with this condition, directly causing thrombosis of hepatic veins or contributing to an underlying prothrombotic state [27]. Hepatic peliosis may be a complication of oral contraceptives, and the lesions resolve with therapy withdrawal [36]. Finally, oral contraceptives have been associated with the risk of developing hepatic adenomas, focal nodular hyperplasia, and haemangiomas [27]. Androgens The risk of liver function tests abnormalities following the use of androgenic hormones is relevant. Elevated aminotransferase levels or cholestasis may be observed not infrequently, while adenomas and even hepatocellular carcinoma may develop, also within a structurally unaltered liver. In fact, a young man with androgen intake for several years has been recently diagnosed with hepatocellular carcinoma at our unit. Following partial resection, alcohol injection, and transarterial embolization, tumour recurrence within an year from the last locoregional procedure has now prompted evaluation for liver transplantation as curative treatment. Gonadal dysfunction in liver diseases The normal function of the hypothalamic–pituitary–gonadal axis is affected in liver disease. Cirrhosis in general may be associated with hypogonadism and signs of feminization, suggesting altered levels of sex hormones. Testicular atrophy, low testosterone levels, decreased libido, infertility, and gynaecomastia are often recognized in men with cirrhosis. In cirrhotic patients, the oestrogen/androgen ratio is usually increased [37]. In vitro studies on isolated Leydig cells, isolated perfused rat testes, and testicular homogenates have all demonstrated reduced testosterone synthesis and concentrations [38]. Alcoholic liver disease, in particular, is associated with a myriad of alterations linked to sex hormones. Clinical signs of hypogonadism are commonly more pronounced in patients with alcoholic liver disease, due to the direct inhibitory effects of alcohol upon testes. Alcoholic liver disease is associated with abnormalities in circulating levels of gonadal steroid hormones. Increasing circulating oestradiol and reduction in testosterone have been found in male patients with alcohol-related hepatic fatty changes, hepatitis and cirrhosis. These findings suggest that both a direct effect of alcohol as well as hepatic dysfunction determine changes in gonadal steroids in men [19]. Haemochromatosis, a genetic disease which defective gene product abnormally modulates the uptake of transferrin by cells, causing excessive iron accumulation and toxicity in the pituitary and the testes [39], normally causes chronic liver disease as well; half of haemochromatosis patients present hypogonadism with testicular atrophy [37]. Liver transplantation, a strategy that has proved to constitute a curative treatment for patients with end stage liver disease as well as acute liver failure, offers a different scenario related to hormone metabolism. Significantly higher levels of prolactin and sex hormone binding globulin have been ascertained in cirrhosis male patients when compared to liver transplant recipients. Furthermore, it has been shown that the percentage of patients with severe erectile dysfunction is significantly greater in patients with cirrhosis vs. transplanted patients, and that sexual dysfunction correlates with more advanced age [40]. Among women, alcohol abuse causes disturbances in the hormonal status and the reproductive performance. Chronic alcohol consumption is associated with hypogonadism, loss of secondary sexual
558
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
characteristics, amenorrhoea and early menopause, due to a reduction in oestrogen and gonadotrophin secretion [37]. Female patients with cirrhosis show significantly lower levels of total testosterone and higher levels of prolactin and delta-4-androstenedione in comparison with patients who have undergone liver transplantation [41]. Metabolic syndrome and the liver Metabolic syndrome, type II diabetes, obesity, and hyperlipidaemia are linked to non-alcoholic fatty liver disease (NAFLD). The metabolic syndrome is characterized by a cluster of metabolic abnormalities including truncal obesity, glucose intolerance, hypertension and dyslipidemia. The challenge endocrinologists face in the diagnosis of NAFLD is that signs and symptoms are frequently absent or nonspecific and can be easily missed. Frequently, these patients are characterized by obesity-related complications such as metabolic syndrome and type II diabetes. Liver fat accumulation may range from steatosis to severe steatohepatitis, with progression into fibrosis, cirrhosis, and a high risk of HCC. If elevated, liver aminotransferases may be helpful in making the diagnosis, but liver disease may exist in the presence of normal transaminases. Although liver ultrasound and MRI can aid the clinician, a liver biopsy is usually necessary to establish the diagnosis of NASH [42]. Insulin resistance is the most important metabolic abnormality of this syndrome and it seems to play a relevant role in the pathogenesis and progression of NAFLD [27]. In this regard, cytokines play a role in the development of insulin resistance. Leptin, for instance, is a cytokine produced by the adipose tissue and is involved in the regulation of food intake. In animal models, leptin deficiency causes metabolic and endocrine disorders including obesity, hypogonadism, hypothyroidism, insulin resistance, and diabetes [27]. Resistin, another cytokine, is a pro-inflammatory agent associated with insulin resistance in patients with type II diabetes. In patients with non-alcoholic steatohepatitis (NASH), high levels of resistin have been reported. Furthermore, the PPAR-activating thiazolidinedione rosiglitazone lowers resistin levels and resistin gene expression in animal models, and has been shown to improve liver function tests, but not fibrosis, in humans [43–45]. Irrespective of body mass index, the presence of type II diabetes increases the risk of NAFLD when compared with subjects with normal glucose levels or impaired glucose tolerance [46]. Type II diabetes may negatively affect the outcome of patients with liver disease, especially in patients with NAFLD, in whom metabolic syndrome increases the risk of cardiovascular diseases, type II diabetes, and NASH [47]. The incidence of NAFLD is increasing worldwide, and cirrhosis and hepatocellular carcinoma may become the leading indication for liver transplantation in the next future. In addition, the risk of developing metabolic syndrome after liver transplantation is well known. At the Multivisceral Transplant Unit of the Padua University Hospital, a study has determined the prevalence of type II diabetes and hypertension in 182 patients with at least five years of follow up after liver transplantation. Diabetes was found in 30% of cases and hypertension in 50% of cases, and were both significantly more frequent in male compared to female liver transplant recipients. Cardiovascular events, observed in 7% of cases, were more frequently seen in patients with features of metabolic syndrome (unpublished data). Growth hormone and metabolic syndrome The metabolic effects of growth hormone include hyperglycemia, hyperinsulineamia and lipolysis, and patients with excess of this hormone may develop features that resemble metabolic syndrome [37]. In patients with hypothalamic or pituitary disease obesity, impaired glucose tolerance, NAFLD, NASH, and cirrhosis have been described [48]. The liver is the major source of circulating insulin-like growth factor-1 (IFG-1) and has been suggested as a major source of at least two of the major binding proteins that modify bioavailability [49]. Growing evidence has revealed that GH as well as IGF-I play an essential role in the liver. Further research is needed to define the mechanisms by which GH and IGF-I exert their effects in the liver [50]. In this regard, IGF-1 levels were demonstrated to correlate with differences in fibrosis in 55 patients with NAFLD: on multivariate analysis, platelet count and IGF-1 showed a significant association with stage 2–3 NAFLD. Although there was no relationship of fibrosis with GH level, decreased GH was significantly associated with stage 2–3 steatosis, while a low
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
559
GH/IGF-1 ratio was found in advanced steatosis. The authors of this study concluded that GH and IGF-1 are associated with hepatic fibrosis and steatosis in NAFLD [51]. Ovarian dysfunction and metabolic syndrome Polycystic ovary syndrome is the most common endocrine abnormality in premenopausal women, and the prevalence of insulin resistance and hyperinsulinaemia is increased in such patients. Clinical features are the result of increased testosterone secretion by ovaries that are generally normally insulin-sensitive, secondary to the higher circulating insulin concentrations. Nevertheless, not all insulin-resistant women have polycystic ovary syndrome and viceversa [52]. Haemostatic abnormalities in endocrine and liver disorders The haemostatic balance is a complex system regulated by several factors, including hormones. There is strong evidence that abnormalities of coagulation and fibrinolysis can be seen in patients with endocrine disorders including hypothyroidism, hyperthyroidism, Cushing’s syndrome, GH-related pituitary dysfunctions, pituitary prolactine-producing adenomas, polycystic ovary syndrome, and primary hyperparathyroidism. Similarly, metabolic syndrome is associated with enhanced coagulation and impaired fibrinolysis. Overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine disorders in general are associated with an elevation in the risk of thrombosis. There is a general consensus that patients with Cushing’ syndrome are at high risk of venous thromboembolism, and prophylaxis with low-molecular-weight heparin should be considered in these cases. Bleeding in overt hypothyroidism can be related to an acquired von Willebrand’s disease type I. Except for metabolic syndrome, however, the number of studies that have been performed analysing haemostasis disorders in patients with endocrine diseases is limited and the number of patients studied is small [53]. Patients with metabolic syndrome are at increased risk of cardiovascular diseases [54], and the syndrome is frequently associated with a prothrombotic state, characterized by increased plasmatic coagulation, reduced fibrinolysis, decreased endothelial thrombo-resistance and platelet hyperactivity, contributing to the development of cardiovascular complications [55,56]. Low-dose aspirin prophylaxis is usually recommended in patients affected by metabolic syndrome, but there are no specific studies of the use of aspirin or anti-platelet agents for the primary prevention of cardiovascular events in these patients [54–56]. Nonetheless, the prophylactic use of low-dose aspirin in the prevention of cardiovascular disease in patients with metabolic syndrome, but without diabetes, as well as in those with endocrine disorders should be considered based on clinical judgement [53]. Statins and the liver Several studies have confirmed that lipid-lowering therapy reduces the risk of cardiovascular events [57], and statins are commonly used for primary and secondary prevention of myocardial infarction, owing to their positive effect on the lipid profile together with their general safety and tolerability, which has been established in thousands of treated patients [58]. Serious adverse events, however, have been reported including myopathy, rhabdomyolisis and elevated transaminase levels, and liver function tests should therefore be monitored before and regularly after starting statin therapy. There is some data however, reporting that abnormalities of liver function tests may be the consequence of statin’s lipid-lowering effect rather than true toxicity to the liver [59,60]. A meta-analysis of randomized controlled trials of statins used for the treatment of hyperlipidaemia or for primary or secondary prevention of cardiovascular disease published nearly ten years ago demonstrated that the proportion of patients with abnormal liver function tests was low (1.14%) in patients taking statins, vs. 1.05% in placebo-treated patients (OR 1.26, 95% CI 0.99–1.62, p ¼ 0.07). Only fluvastatin was associated with a significant increased in the odds of having liver function test abnormalities (fluvastatin 1.13% vs. placebo 0.29%, OR 3.54, 95% CI 1.1–11.6, p ¼ 0.04). The authors concluded that pravastatin, lovastatin, and simvastatin at low-to-moderate doses were not associated with a significant risk of liver function test abnormalities [58]. Moreover, coexisting transaminase elevation in non-alcoholic fatty liver disease and stable hepatitis C and B viral infections is not a contraindication to statin use [61].
560
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
Oral hypoglycemic agents and the liver Type II diabetes is often associated with metabolic syndrome, and overt diabetes mellitus is present in 21–40% of patients with cirrhosis. The prevalence of glucose metabolism disorders was reported to be 79% in a small group of patients with cirrhosis, of whom 19% had type II diabetes. Overall, glucose metabolism disorders were subclinical in 415 of cases [62]. Metformin, an insulin sensitizer which decreases insulin secretion and ameliorates the hyperinsulinaemic status, has been studied extensively studied in diverse scenarios. An interesting study was performed on 82 patients with liver cirrhosis and type II diabetes, 41 of whom were on metformin and 41 without metformin treatment. Metformin was found to be independently related to overt hepatic encephalopathy in patients with type II diabetes and high risk of encephalopathy, while it was shown to inhibit glutaminase activity in vitro, which could theoretically be protective against encephalopathy in the same study [63]. From a large series of 44.406 patients with type II diabetes exposed to oral antidiabetic agents, 605 were identified as having liver disease, and of this subgroup, 186 had non-symptomatic, mild, and transient liver disorders, 249 had a predisposing condition, and 113 had another cause of liver disease. A total of 57 cases were possibly drug-induced, with an incidence rate of 5/10.000 personyears (3.9–6.5). Of these, 11 cases were attributed to other drugs and eight were attributed to fatty liver disease of diabetes. Oral antidiabetic agents were continued in 51 of these 57 cases. In conclusion in this large population of patients with type II diabetes treated with oral antidiabetic agents, the incidence of liver disease was high, but most cases involved other diseases that may cause liver disease [64]. Conclusions Being the liver involved in such a myriad of metabolic processes, it is clearly a key component that has both an impact on the endocrine system, as well as being an inevitable target during the course of endocrine disorders or the treatments they require. Not only infrequent disorders such as haemochromatosis and infiltrative malignancies are able to cause hepatic and endocrine derangements, but present-day epidemic diseases such as metabolic syndrome impose the need for the integration between the two fields both in terms of diagnosis as well as therapy. Clearly, it is ever more important to be prepared to deal with multiple drug interactions, and the effects of obesity and insulin resistance, in a worldwide population that tends to be aged and have numerous comorbidities.
Practice points: The liver and its pleotropic functions play a fundamental role in regulating metabolism, and is also an inevitable target of multiple metabolic disorders. An unabridged list of pharmacological agents, including not only prescription medication but also herbal preparations and over-the-counter drugs, must be a fundamental component of the initial evaluation of hepatic disorders in the presence of endocrine abnormalities. Hypo- and hyperthyroidism are frequently associated with hepatic alterations, and thyroid diseases, as well as therapeutic agents used to treat these endocrine disorders must be excluded in transaminase elevation of unknown cause. Adrenal insufficiency should be promptly identified and treated in decompensated cirrhosis patients, especially during episodes of sepsis, as this complication increases mortality. In cases of alcohol abuse and endocrine abnormalities such as feminization in men, sex hormone panel must be firstly evaluated, but special attention should be drawn to excluding an underlying liver disease. Patients with metabolic syndrome, the pandemia of the present and future centuries, must be evaluated diligently in terms of liver damage, in order to exclude steatosis, fibrosis, cirrhosis and hepatocellular carcinoma.
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
561
Research agenda: Although direct gonadal inhibitory effects of alcohol have been widely demonstrated in the mouse animal model, further studies are needed to clarify the role of this agent vs. the importance of liver damage induced by alcohol. In the era of increasing number of patients being transplanted because of non-alcoholic steatohepatitis (NASH) leading to cirrhosis and hepatocellular carcinoma (HCC), and given the high incidence of post-transplant metabolic syndrome, future studies will be needed to establish strategies to avoid graft loss, increased cardiovascular risk post-transplant, and to eventually re-evaluate allocation criteria. Studies on decompensation in cirrhosis patients, especially during episodes of sepsis, will further characterize adrenal insufficiency in these patients and will provide clinicians with new therapeutic protocols to apply in these circumstances.
Conflict of interest statement No conflict of interest.
Acknowledgements Dr. Giacomo Germani, MD, PhD and Dr. Kryssia Rodríguez-Castro, MD, PhD.
References [1] Malik R, Hodgson H. The relationship between the thyroid gland and the liver. QJM 2002;95:559–69. [2] Laycock MA, Pascuzzi RM. The neuromuscular effects of hypothyroidism. Semin Neurol 1991;11:288–94. [3] Kinney EL, Wright RJ, Caldwell JW. Value of clinical features for distinguishing myxedema ascites from other forms of ascites. Comput Biol Med 1989;19:55–9. [4] Baker A, Kaplan M, Wolfe H. Central congestive fibrosis of the liver in myxedema ascites. Ann Intern Med 1972;77:927–9. [5] Klein I, Levey GS. Unusual manifestations of hypothyroidism. Arch Intern Med 1984;144:123–8. [6] Van Steenbergen W, Fevery J, De Vos R, Leyten R, Heirwegh KP, De Groote J. Thyroid hormones and the hepatic handling of bilirubin. I. Effects of hypothyroidism and hyperthyroidism on the hepatic transport of bilirubin mono- and diconjugates in the Wistar rat. Hepatology 1989;9:314–21. [7] Gaitan E, Cooper DS. Primary hypothyroidism. Curr Ther Endocrinol Metab 1997;6:94–8. [8] Thompson Jr P, Strum D, Boehm T, Wartofsky L. Abnormalities of liver function tests in tyrotoxicosis. Mil Med 1978;143: 548–51. [9] Doran GR. Serum enzyme disturbances in thyrotoxicosis and myxoedema. J R Soc Med 1978;71:189–94. [10] Sola J, Pardo-Mindán FJ, Zozaya J, Quiroga J, Sangro B, Prieto J. Liver changes in patients with hyperthyroidism. Liver 1991; 11:193–7. [11] Elias R, Dean DS, Barsness GW. Hepatic dysfunction in hospitalized patients with acute thyrotoxicosis: a decade of experience. Endocrinology 2012:1–6. [12] Williams KV, Nayak S, Becker D, Reyes J, Burmeister LA. Fifty years of experience with propylthiouracil-associated hepatotoxicity: what have we learned? J Clin Endocrinol Metab 1997;82:1727–33. [13] Levy M. Propylthiouracil hepatotoxicity. A review and case presentation. Clin Pediatr (Phila) 1993;32:25–9. [14] Golding PL, Smith M, Williams R. Multisystem involvement in chronic liver disease. Studies on the incidence and pathogenesis. Am J Med 1973;55:772–82. [15] Elta GH, Sepersky RA, Goldberg MJ, Connors CM, Miller KB, Kaplan MM. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983;28:971–5. [16] Silveira MG, Mendes FD, Diehl NN, Enders FT, Lindor KD. Thyroid dysfunction in primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease. Liver Int 2009;29:1094–100. [17] Pateron D, Hartmann DJ, Duclos-Vallee JC, Jouanolle H, Beaugrand M. Latent autoimmune thyroid disease in patients with chronic HCV hepatitis. J Hepatol 1993;17:417–9. [18] Huang MJ, Liaw YF. Clinical associations between thyroid and liver diseases. J Gastroenterol Hepatol 1995;10:344–50. [19] Burra P, Franklyn JA, Ramsden DB, Elias E, Sheppard MC. Severity of alcoholic liver disease and markers of thyroid and steroid status. Postgrad Med J 1992;68:804–10. [20] Burra P, Fitch NJ, Kapadi A, Franklyn JA, Sheppard MC, Ramsden DB, et al. The effects of ethanol, 3,5,30 -triiodothyronine (T3) and oestradiol (E2) on thyroid hormone nuclear receptor expression in human hepatocyte primary cultures. Alcohol Alcohol 1995;30:219–21.
562
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
[21] Huang MJ, Liaw YF. Thyroxine-binding globulin in patients with chronic hepatitis B virus infection: different implications in hepatitis and hepatocellular carcinoma. Am J Gastroenterol 1990;85:281–4. [22] L’Age M, Meinhold H, Wenzel KW, Schleusener H. Relations between serum levels of TSH, TBG, T4, T3, rT3 and various histologically classified chronic liver diseases. J Endocrinol Invest 1980;3:379–83. [23] Oren R, Sikuler E, Wong F, Blendis LM, Halpern Z. The effects of hypothyroidism on liver status of cirrhotic patients. J Clin Gastroenterol 2000;31:162–3. [24] Koh LK, Greenspan FS, Yeo PP. Interferon-alpha induced thyroid dysfunction: three clinical presentations and a review of the literature. Thyroid 1997;7:891–6. [25] Flohr F, Harder J, Seufert J, Blum HE, Spangenberg HC. Hypothyroidism in patients with hepatocellular carcinoma treated by transarterial chemoembolization. Hepatology 2008;47:2144. [26] Tamaskar I, Bukowski R, Elson P, Ioachimescu AG, Wood L, Dreicer R, et al. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol 2008;19:265–8. [27] Maheshwari A, Thuluvath PJ. Endocrine diseases and the liver. Clin Liver Dis 2011;15:55–67. [28] Boulton R, Hamilton MI, Dhillon AP, Kinloch JD, Burroughs AK. Subclinical Addison’s disease: a cause of persistent abnormalities in transaminase values. Gastroenterology 1995;109:1324–7. [29] Fede G, Spadaro L, Tomaselli T, Privitera G, Germani G, Tsochatzis E, et al. Adrenocortical dysfunction in liver disease: a systematic review. Hepatology 2012;55:1282–91. [30] Marik PE. Adrenal-exhaustion syndrome in patients with liver disease. Intensive Care Med 2006;32:275–80. [31] O’Beirne J, Holmes M, Agarwal B, Bouloux P, Shaw S, Patch D, et al. Adrenal insufficiency in liver disease – what is the evidence? J Hepatol 2007;47:418–23. [32] Stewart PM, Burra P, Shackleton CH, Sheppard MC, Elias E. 11 Beta-hydroxysteroid dehydrogenase deficiency and glucocorticoid status in patients with alcoholic and non-alcoholic chronic liver disease. J Clin Endocrinol Metab 1993;76:748–51. [33] Lindgren A, Olsson R. Liver damage from low-dose oral contraceptives. J Intern Med 1993;234:287–92. [34] Kreek MJ. Female sex steroids and cholestasis. Semin Liver Dis 1987;7:8–23. [35] Reyes H, Gonzalez MC, Ribalta J, Aburto H, Matus C, Schramm G, et al. Prevalence of intrahepatic cholestasis of pregnancy in Chile. Ann Intern Med 1978;88:487–93. [36] Weinberger M, Garty M, Cohen M, Russo Y, Rosenfeld JB. Ultrasonography in the diagnosis and follow-up of hepatic sinusoidal dilatation. Arch Intern Med 1985;145:927–9. [37] Karagiannis A, Harsoulis F. Gonadal dysfunction in systemic diseases. Eur J Endocrinol 2005;152:501–13. [38] De Maria N, Colantoni A, Van Thied D. The liver and endoscrine function. In: Becker KL, Bilezikian John P, Bremner William J, editors. Principles and practice of endocrinology and metabolism. Wilkins; 2000. p. 1870–85. [39] Cox TM, Kelly AL. Haemochromatosis: an inherited metal and toxicity syndrome. Curr Opin Genet Dev 1998;8:274–81. [40] Burra P. Sexual dysfunction after liver transplantation. Liver Transpl 2009;(15 Suppl. 2):S50–6. [41] Burra P, Germani G, Masier A, De Martin E, Gambato M, Salonia A. Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure? Transplantation 2010;89:1425–9. [42] Lomonaco R, Chen J, Cusi K. An endocrine perspective of nonalcoholic fatty liver disease (NAFLD). Ther Adv Endocrinol Metab 2011;2:211–25. [43] Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, et al. Increased serum resistin in nonalcoholic fatty liver disease is related to liver disease severity and not to insulin resistance. J Clin Endocrinol Metab 2006;91:1081–6. [44] Ratziu V, Charlotte F, Bernhardt C, Giral P, Halbron M, Lenaour G, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 2010; 51:445–53. [45] Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature 2001;409:307–12. [46] Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005;22:1141–5. [47] Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37:917–23. [48] Adams LA, Feldstein A, Lindor KD, Angulo P. Nonalcoholic fatty liver disease among patients with hypothalamic and pituitary dysfunction. Hepatology 2004;39:909–14. [49] Donaghy A, Ross R, Gimson A, Hughes SC, Holly J, Williams R. Growth hormone, insulinlike growth factor-1, and insulin like growth factor binding proteins 1 and 3 in chronic liver disease. Hepatology 1995;21:680–8. [50] Takahashi Y. Essential roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the liver. Endocr J 2012;59: 955–62. [51] Ichikawa T, Nakao K, Hamasaki K, Furukawa R, Tsuruta S, Ueda Y, et al. Role of growth hormone, insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 in development of non-alcoholic fatty liver disease. Hepatol Int 2007;1: 287–94. [52] Sam S, Dunaif A. Polycystic ovary syndrome: syndrome XX? Trends Endocrinol Metab 2003;14:365–70. [53] Franchini M, Lippi G, Manzato F, Vescovi PP, Targher G. Hemostatic abnormalities in endocrine and metabolic disorders. Eur J Endocrinol 2010;162:439–51. [54] Cornier MA, Dabelea D, Hernandez TL, Lindstrom RC, Steig AJ, Stob NR, et al. The metabolic syndrome. Endocr Rev 2008; 29:777–822. [55] Alessi MC, Juhan-Vague I. Metabolic syndrome, haemostasis and thrombosis. Thromb Haemost 2008;99:995–1000. [56] Mina A, Favaloro EJ, Koutts J. Hemostatic dysfunction associated with endocrine disorders as a major risk factor and cause of human morbidity and mortality: a comprehensive meta-review. Semin Thromb Hemost 2007;33:798–809. [57] Stamler J, Wentworth D, Neaton JD. Prevalence and prognostic significance of hypercholesterolemia in men with hypertension. Prospective data on the primary screenees of the Multiple Risk Factor Intervention Trial. Am J Med 1986;80: 33–9. [58] de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy 2004;24: 584–91.
P. Burra / Best Practice & Research Clinical Gastroenterology 27 (2013) 553–563
563
[59] Roberts WC. Getting more people on statins. Am J Cardiol 2002;90:683–5. [60] Tolman KG. The liver and lovastatin. Am J Cardiol 2002;89:1374–80. [61] Gillett Jr RC, Norrell A. Considerations for safe use of statins: liver enzyme abnormalities and muscle toxicity. Am Fam Physician 2011;83:711–6. [62] García-Compeán D, Jáquez-Quintana JO, Lavalle-González FJ, Reyes-Cabello E, González-González JA, Muñoz-Espinosa LE, et al. The prevalence and clinical characteristics of glucose metabolism disorders in patients with liver cirrhosis. A prospective study. Ann Hepatol 2012;11:240–8. [63] Ampuero J, Ranchal I, Nuñez D, Díaz-Herrero Mdel M, Maraver M, del Campo JA, et al. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279. [64] Jick SS, Stender M, Myers MW. Frequency of liver disease in type 2 diabetic patients treated with oral antidiabetic agents. Diabetes Care 1999;22:2067–71.