Some Endocrine Changes in Liver Disease G

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Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from POSTGRAD. MED. J. (I963), 39, 205

SOME ENDOCRINE CHANGES IN LIVER DISEASE G. A. MARTINI, M.D. Assoc. Professor of Medicine, University of Hamburg (Germany)

AMONGST the numerous metabolic functions of the altered distribution of secondary hair is the liver are those concerned with the catabolism constitutionally conditioned or whether it is the or inactivation of hormones. One would therefore result of liver disease. Since Chvostek described expect to find liver disease frequently accompanied the 'habitus' known by his name it has not been by endocrine disturbances; and attempts to corre- possible to determine whether or not men with late certain liver disease with disturbances in this type of constitution are more susceptible to endocrine function are not new. In addition, the development of cirrhosis. It is therefore very there are certain features of liver disease such as important to question patients about their hair the 'characteristic' skin changes which are distribution in the 'pre-cirrhotic' phase. Many attributed to altered hormone metabolism. patients can provide evidence and often photo- The close relationship between liver disease and graphs to prove that they never had a heavy the gonads appears to be obvious. In the male growth of pectoral, axillary or pubic hair before there is gynaecomastia and an alteration in the developing cirrhosis. hair distribution with loss of Women with chronic liver secondary axillary disease usually have by copyright. and chest hair and a female distribution of pubic amenorrhaea or dysmenorrhcea and may have hair. Loss of libido, impotence and testicular cystic mastitis or acne. Sterility is the rule and atrophy complete the characteristic picture of conception is very rare. In certain age groups, hormonal disturbances in the human male with about puberty (Bearn, Kunkel and Slater, 1956; chronic liver disease. Oligospermia is common Waldenstr6m, 1952) and after the menopause (Voegt and Weller, 1959). Prostatic hyper- (Alsted, 1947; Cattan, Vesin and Bodin, I957; trophy in men with chronic liver disease is rare Martini and D6lle, I960), women are prone to (Stumpf and Wilens, I953). The incidence of develop a peculiar form of hepatitis of unknown these endocrine disturbances varies with a chronic course and with remarkably aetiology 'post- http://pmj.bmj.com/ as between different countries. Gynaecomastia and necrotic' cirrhosis. Altogether the sex ratio of testicular atrophy, a combination also known as postnecrotic cirrhosis in women to men is 3: I, the Silvestrini-Corda syndrome after the authors in contrast with Laennecs's cirrhosis, which is who first described it (Corda, I925; Silvestrini, preponderant in men. Women who develop 1926), was found by Lloyd and Williams (1948) to virus hepatitis during the menopause are especially occur in 42% of 55 men with cirrhosis of the susceptible to the development of postnecrotic liver. The same workers reported 75% incidence cirrhosis. of testicular atrophy in their patients. However, Both men and women with chronic liver on September 28, 2021 by guest. Protected the incidence of gynacomastia in our own cases disease develop certain vascular changes in the and in others, as for instance in England, is skin, such as arterial spiders, 'white spots' (Martini distinctly low. The same applies to other signs of and Staubesand, I953; Martini, I955) and palmar chronic liver disease such as parotid swelling erythema. These skin changes occur with almost and Dupuytren's contracture (Davidson, Sherlock, equal frequency in pregnant women and disappear Summerskill, Turner and Wolfe, I960). It is again soon after parturition. These observations quite possible that alcoholism alone, or rather the led Bean, (1945) to regard the vascular changes as accompanying malnutrition, like that in prisoners a manifestation of 'hypercestrogenism'. An of war during the period of nutritional re-feeding increase in cestrogens is a normal feature of (Klatskin, Salter and Humm, 1947; Kark, Morey pregnancy. In chronic liver disease the liver is and Paynter, 1951), plays a decisive part in the said to be incapable of inactivating cestrogens; development of these signs. 'Alcoholic' cirrhosis hence the (estrogen level in the blood rises. This predominates in the American cases, but is not interpretation is disarmingly simple. It was indeed nearly so common in England or in Germany. possible to induce the development of arterial Moreover it is difficult to determine whether spiders and palmar erythema in one third of 30 Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from 206 POSTGRADUATE MEDICAL JOURNAL April I963 patients with cirrhosis by the administration of aestrogens were disturbed there would still be the oestrogenic substances, but two thirds of the intestine to compensate for it. According to patients showed no such response (Bean, 1958). Sandberg and Slaunwhite (I957), there exists an Nor have such phenomena been observed in entero-hepatic circulation of oestrogens not only patients with carcinoma of the prostate who have in animals but also in man. When radioactive received very large doses of oestrogens. In any oestrogens were given, 50% of the radioactivity case a purely hormonal factor would not explain .was recovered in the bile, but only 7% excreted in the localisation of the spider naevi and their the fieces. Up to 80% was excreted in the urine. distribution. They are practically confined to the It is not yet decided whether oestrogens are so-called exposed parts of the skin (face, neck and absorbed as free oestrogens after hydrolyzation in arms). This localization suggests that beside the the intestine or in conjugated form. It was shown hormonal or 'internal' factor in the production of recently that in man the intestine is able to arterial spiders, an 'external' factor may be conjugate free aestrogens which were brought into operating: the structure and function of the the intestinal lumen at operation (Diczfalusy, affected portion of the skin and of its smallest Frankson and Martinsen, I96I). A retafdation vessels and their altered reaction to the action of in this bilio-entero-hepatic cycle was postulated sunshine, wind and light (Martini, I955). by Rupp, Cantarow, Rakoff and Paschkis (I951) The most important question, however, is and Dohan, Richardson, Bluemle and Gyorgy whether there is actually an cestrogenic excess in (1952), to account for the disturbed oestrogen patients with chronic liver disease and if so, metabolism in patients with cirrhosis. whether there is any correlation between the A further difficulty arises from the indecision cestrogen levels and the clinical signs such as about which of the various known aestrogenic gynaecomastia, altered hair distribution and skin hormones is to be regarded as the primary hormone. changes. Oestradiol, oestrone and oestriol have all been nominated. But these three represent only 20% The Metabolism of (Estrogens of all aestrogens. Brown and Marrian

(1957)by copyright. Our knowledge about the nature and quantity of suggested the following metabolic pathways for circulating oestrogens in the plasma of patients these oestrogens: with liver disease is scanty, and therefore the CEstradiol-I7 P evidence in favour of the before mentioned 'hypercestrogenism' in liver disease remains CEstrone circumstantial (Diczfalusy, I962). In pregnancy the ratio unconjugated (free) to conjugated I6o-Hydroxycestrone I6B-Hydroxyoestrone I7-p3-oestradiol was higher than similar ratios for oestrone and oestriol. If this could be confirmed CEstriol i6 epi-(Estriol in patients with liver disease it could well be that In addition, until the last few years the onlyhttp://pmj.bmj.com/ this shift towards free oestradiol accounts for the method available for estimating cestrogens was 'hyperoestrogenism' (Diczfalusy, I962). the biological method of the Allen-Doisy test; Since Zondek's work (i934) it has been known this was the method used in most of the reported that the healthy liver plays an important part in studies of oestrogen excretion in liver disease. the inactivation of oestrogenic hormones. In this Since then new biochemical methods have been process conjugation of the hormones with developed, and it is expected that they will acid or acid is more glucuronic sulphuric particularly provide accurate quantitative information. on September 28, 2021 by guest. Protected important. However, it is still not decided Comparison of the two methods is rendered even whether conjugation and inactivation are one and more difficult by the fact that they estimate the same thing or not (Cameron, 1957 a & b). It has different oestrogenic fractions. The Allen-Doisy been found that under certain conditions the test estimates oestradiol rather than oestrone or glucuronic acid ester of the hormones is apparently oestriol, whereas Brown's biochemical method as active as the free hormones. Some conjugates, estimates all three hormones, (I955). Although when administered, are easily hydrolyzed in the much work has been done in the past there body. In contrast to other steroid hormones is no clear answer yet to the question whether the which are inactivated by enzymatic reduction excretion pattern of oestrogens differs quantita- before conjugation, oestrogens are conjugated in tively and qualitatively in patients with liver the active form. disease from that in normals. It seems doubtful whether the estimation of free The results obtained with the biochemical and conjugated oestrogens can in any way yield method are in direct contrast with those obtained more information about disturbed liver function. by means of the biological assay (Bennett, Even if this particular liver function of conjugating Baggenstoss and Butt I950; Dohan and others, Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from April I963 MARTINI: Some Endocrine Changes in Liver Disease 207 1952; Glass, Edmonson and Soil, I944; Rupp and increase in the basophil cells of the pituitary and others, I951), which had shown an increase in adrenal atrophy. total cestrogen excretion in nearly half of the Again it will be necessary to consider the patients with cirrhosis, the hormones appearing variety in 'normal' levels, depending on race, in the urine mainly as free oestrogens. This was nutrition, age etc. For instance normal Bantu also shown by Miiller (1958) using a fluorimetric males are reported to have a much higher oestrogen method. Cameron (1957) was not able to confirm excretion than normal white males in South these results using Brown's method. He found, Africa. The aestradiol fraction was particularly as others had done before him, (Pincus, Rakoff, increased in these Bantus. In Bantus with chronic Cohn and Tumen, 195i) that there was no liver disease the cestradiol fraction further increased. increase in free cestrogen excretion in his group In white men with liver disease it was the of 12 patients with cirrhosis, except in 2. His most cestriol fraction which increased. One can specu- remarkable finding in half of his patients was an late whether malnutrition causes an increase of increase in the proportion of cestriol excreted with 'normal' cestrogen levels and/or changes its a corresponding reduction in the amounts of pattern and moreover, if this increase in turn cestrone and cestradiol. This was the result in causes liver disease and cancer with breast measuring the excretion of endogenous cestrogens. changes which are so frequent in Bantus (Bloom- When larger amounts of oestradiol were adminis- berg and others, 1958; quoted in Diczfalusy and stered in patients with severe liver disease a Lauritzen, I96I. 'shift' towards increased oestradiol excretion took place (Lyngbye and Mogensen, I96I). The Metabolism of Androgen The discrepancy between the results of the The original findings of Fraser, Forbes, Albright, biological and the biochemical assays can be Sulkowitch and Reifenstein (1941), that the explained by postulating that certain of the newly excretion of I7-ketosteroids is diminished in the identified cestrogenic hormones, such as epioestrol urine of patients with chronic liver disease have or i6a-hydroxyoestrone, are responsible for the repeatedly been confirmed and are considered endocrine stigmata in patients with cirrhosis: the firmly established (Peterson, I960). Birke and by copyright. cestrogenic activity of these substances would be others found the urinary output of I7-ketosteroids apparent in the biological assay, but not in the in cirrhotics both male and female as low as in biochemical method employed. adrenal cortical insufficiency (Birke 1962). Even In fact, i6a-hydroxyoestrone seems to be just as after testosterone administration the urinaryoutput active as oestriol (Loraine, 1958), and has been of I7-ketosteroids is much decreased in patients demonstrated in considerable amounts in the with liver disease. Whereas some authors urine of pregnant women (Brown and Marrian, (Williams, Cantarow, Paschkis and Havens, 1951; I957). An inhibition of the conversion of cestradiol Birke, found no decreased to convert

I962) ability http://pmj.bmj.com/ into cestriol was demonstrated by Lyngbye and testosterone to I7-ketosteroids, some others Mogensen (I96I). If such an inhibition occurred thought it to be disturbed (West, Tyler, Brown in the conversion of i6o-hydroxyoestrone into and Samuels, I95I). Both the conjugation with oestriol the former substance could accumulate glucuronic acid and sulphuric acid are disturbed without being estimated in the urine by the (Birke, Diczfalusy and Plantin, 1959), but no biochemical method. free 17-ketosteroids were excreted (Bongiovanni It is important, however, not to seek facile and Eisenmenger, 195I). Apparently both the explanations until reliable quantitative results I7-ketosteroids originating in the adrenal cortex on September 28, 2021 by guest. Protected about aestrogen excretion have been obtained. It and in the testis are diminished (Cameron, 1957). may then perhaps be possible to establish that a However, this diminution is probably not alone definite correlation exists between the particular due to faulty conversion of testosterone to 17- endocrine features in liver disease and both the ketosteroid, but to reduced androgen production quantity and the quality of cestrogens excreted. as well. The resultant imbalance between andro- The morphological changes in the endocrine gens and cestrogens could also account for the organs of patients with cirrhosis nevertheless 'hyperoestrogenism' even in those males who have suggest a strong cestrogenic effect (Bennett and a normal oestrogen output in the urine. For there others, 1950; Barr and Sommers, 1957): approxi- is an undoubted antagonism between oestrogens mately half of 30 female patients had adenofibrosis and the other steroid hormones (Szego and of the breast or cystic mastitis and endometrial Roberts, 1953). The diminution in androgen hyperplasia. Two thirds of 70 male patients production still requires explanation. An excess examined showed the 'characteristic' changes in of oestrogens might depress androgen production the prostate and testis. Other remarkable by inhibiting the production and release of findings in these male patients were a marked gonadotropin from the pituitary gland. The Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from 208 POSTGRADUATE MEDICAL JOURNAL April I963 urinary gonadotropin excretion has been found to blood than in the arterial blood after intravenous be greatly reduced in some cases (Voegt and administration of radioactive hydrocortisone. Weller, I958). Or, there could be a primary In patients with chronic liver disease the plasma reduction in androgen production owing to levels of free corticosteroids and its rise after malnutrition with protein deficiency which ACTH administration were the same as in normal frequently accompanies alcoholic cirrhosis. subjects (Englert, Brown, Wallach and Simon, Reduced pituitary function in malnutrition was I957; Birke and others, 1959). However, hydro- reported by Fletcher and Brown (I959). Another cortisone administered to patients with liver disease possibility is the direct damaging effect of alcohol disappeared much more slowly from the blood on the endocrine system; for the 'endocrine stream and appeared in the urine in much lower stigmata' are undoubtedly more common in concentration than in normal subjects. Sur- alcoholic cirrhosis than in posthepatitic cirrhosis. prisingly, cortisone, corticosterone and tetrahydro- But this is speculation. cortisone were found to disappear from the blood stream with equal rapidity in patients with liver Adrenal Hormones disease and in normal subjects (Englert and The great deal of interest aroused in recent others, 1957; Peterson, I960). These findings are years by the adrenal hormones has also directed best explained by the existence of a specific TPNH- attention to the relationship between adrenal dependent enzyme, theA-4-hydrogenase, which cortical hormones and the liver. There are reduces cortisol to dihydrocortisol. Dihydro- certain clinical observations which suggest distur- cortisol is then further reduced to tetrahydro- bances in adrenal hormone metabolism but the cortisol. These reduced forms are conjugated in exact nature of these disturbances has not yet the liver with glucuronic acid or sulphuric acid been defined. Bearn and coworkers (I956) have and then excreted in the urine. Apparently it is described signs of 'hypercorticism' especially in only the enzymatic reduction which is disturbed the peculiar form of chronic hepatitis which in liver disease and not the conjugation with occurs in girls and young women. The signs glucuronic acid. When the combinations

'right' by copyright. include acne, moonface, striae, and more rarely are presented as for instance tetrahydrocortisol, hirsutism. These girls often have amenorrhoea conjugation proceeds normally (Brown, I957). and react to oestrogen administration by rise in The amount of urinary unconjugated steroids in the bilirubin level. Waldenstr6m (1952) has patients with liver disease seems to be slightly reported similar findings. The incidence of each raised above normal and consists mainly of 6-3- of the signs ascribed to adrenal cortical hyper- hydrocortisol (Katz, Lipman, Frantz and Jailer, function is so variable that there is a good deal I962). of justified doubt about the existence of such a Thus it appears that the rate of cortisol meta- syndrome. (Willcox and Isselbacher, I96I). bolism is decreased in liver disease. The

bodyhttp://pmj.bmj.com/ This group of patients does more commonly pool of cortisol is normal or slightly increased, share other signs such as polyarthritis and whereas the turnover rate of the pool is about hypergammaglobulinaemia, rarely the LE-cell; and half normal (Peterson, I960). This means that in it has therefore been suggested that an auto- patients with liver disease the physiologic action immune pathological process may be involved of cortisol is prolonged. This in turn will inhibit (Mackay, I96I). Incidentally, these patients corticotropin secretion and thus consequently lead respond particularly well to cortisone treatment. to the depression ofcortisol synthesis and secretion. details the treatment of liver Further about These patients-although seemingly being on September 28, 2021 by guest. Protected disease with corticosteroids will not be discussed 'eucorticoid'-actually have an adrenal cortical here and the reader is referred to the paper by insufficiency as regards the quantity of cortisol Goldgraber and Kirsner (1959). synthesized (Schedl, 1962). Since the diseased Recent observations have shown the importance liver has partly lost its capacity to inactivate of the liver in the elimination of exogenously cortisol the plasma level remains within the normal administered hydrocortisone. Only about % range. It has frequently been noted that the of the free form of this hormone appears in the adrenal glands of patients with cirrhosis are urine. About 3% is excreted as unconjugated small in size with narrow cortices and a decreased metabolites, 80 to 90% appears as conjugated, lipoid content (Barr and Sommers, 1957). We water-soluble metabolites (Schedl, I962). In mice realise then that the liver together with the about 70% of labelled hydrocortisone was found adrenal and the pituitary plays an important part in the liver within five minutes of administration. in the corticosteroid homceostasis of the organism Plager, Tyler, Hecht and Samuels (I954) have (Birke, I962). reported similar findings in man. They detected These observations are particularly interesting much less radioactivity in the hepatic venous in comparison with rather different recent findings Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from April I963 MARTINI: Some Endocrine Changes in Liver Disease 209 in relation to the other equally important adrenal which had proved ineffective before adrenal- hormone, aldosterone (Koczorek and Wolff, I959). ectomy. Aldosterone plays a very special role in the This operation has been rendered obsolete by pathogenesis of ascites. The patients with cirrhosis the use of aldosterone antagonists. This will not lose the ability to excrete sodium and water at be discussed here but the reader is referred to some particular point of time. Sodium and water a recent monograph (Bartter, I960). then undergo excessive reabsorption by the renal As mentioned before, adrenal factors are not tubules. Sodium reabsorption is largely influenced primarily responsible for the disturbances in by aldosterone which is excreted in the urine in water and electrolyte balance in patients with greater than normal amounts in cirrhotic patients chronic liver disease. Preedy and Aitken with ascites (Luetscher and Johnson, 1954; (1956 a & b) have shown that the administration Wolff, Koczorek and Buchborn, 1958). However, of oestriol is followed by well marked sodium and as other patients with oedema but with normal water retention in cirrhotic patients with ascites. liver function also excrete excessive quantities of Cirrhotic patients without ascites behaved like aldosterone in the urine, it seems that aldosterone normal subjects and showed no sodium or water is probably not solely and primarily responsible retention when given aestriol. They concluded for the development of ascites. that the salt-retaining action of aestriol depended Normally 60% of the endogenous production mainly on the blood-flow through the liver and of aldosterone is excreted as a glucuronic acid only secondarily on disturbances in liver cell conjugate oftetrahydroaldosterone which is biologi- function. Recently Layne, Meyer, Vaishwanar cally inactive; about 20% is excreted as the so- and Pincus (I962) showed that aldosterone called 3-oxo-conjugate which can be converted secretion could be increased by oestrogen admini- to aldosterone by acidification of the urine at stration. If the same occurred in patients with pH i (the so-called pH i extractable conjugate). liver disease, this could explain the salt-retaining Only 0.2% of the total is excreted as free aldo- effect of cestrogen. sterone. About 20% of the excreted metabolites On the whole, the interdependence of hormones are not yet identified (Koczorek, I962). Both ofthe and their metabolites will certainly influence the by copyright. major metabolites of aldosterone are formed in regulation of steroid metabolism and makes it the liver. In patients with chronic liver disease the even more difficult to judge the specific action of altered metabolism of aldosterone is characterized one hormone. by an increased aldosterone secretion rate and a In normals, for instance, the oestrogens increase decreased rate of plasma clearance, the plasma the binding of cortisol to the protein 'transcortin' half-life time of labelled steroid being 68 minutes (an a-globulin) and, if this is saturated, to plasma against 35 minutes in normals it is further albumin. This means that less free or active, and characterized by an increase in the proportion of more protein-bound or inactive cortisol is circu- aldosterone which is metabolized to the 3-oxo- lating (Mills, Schedl, Chen and Bartter, 1960). http://pmj.bmj.com/ conjugate and a decrease in the proportion which (Estrogens equally prolong the plasma half-life is converted to tetrahydroaldosterone (Coppage, of cortisol but not of the dihydro or tetrahydro Island, Cooner and Liddle, I962). The data on compounds of this steroid; besides they decrease aldosterone secretion, however, are somewhat the synthesis rate of cortisol (Peterson, Nokes, conflicting. Not in all investigations was the Chen and Black, I960). Thus it appears that this secretion rate found to be increased, but sometimes 'oestrogen-effect' in persons with normal livers is to be decreased. This could be similar to the disturbed cortisol metabolism perhaps explained very on September 28, 2021 by guest. Protected by the different degree of impaired liver function. in patients with liver disease. Could it be that the Thus in patients with cirrhosis and ascites the aldo- supposed 'hypercestrogenism' in patients with sterone levels in urine are usually markedly cirrhosis accounts for this? Eymer, Schwarz and increased whereas in patients without ascites Weinges, (1961) reported that the 'oestrogen- normal or only slightly raised levels are found. effect' is missing in patients with chronic liver In the belief that the adrenals play a dominant disease. Cortisol did not increase after admini- role in the development and maintenance of stration of cestriol. Biicher suggested that this ascites surgeons have undertaken bilateral adrenal- might be due to the lack of proteins in cirrhosis ectomy on individual patients who had failed to (discussion of Eymer's paper). respond to medical efforts at inducing diuresis Birke (1962) recently has stressed the fact that (Marson, 1954; Giuseffi, Werk, Larson, Schiff and different hormones can act differently on the Ellioth, 1957). After operation there was a sodium catabolism of steroids by enhancing (oestrogens, diuresis but no definite water diuresis and the hyperthyroidism) or diminishing (androgens, reac:umulation of ascites was prevented only by hypothyroidism) the ability of the normal liver to use of diuretics and a low sodium diet-measures act on the A4-3-ketosteroids, or, vice versa, on Postgrad Med J: first published as 10.1136/pgmj.39.450.205 on 1 April 1963. Downloaded from 2IO POSTGRADUATE MEDICAL JOURNAL April 1963 the side chain. The implication of these observa- (1958) found no difference between the anti- tions on the steroid catabolism in disturbed liver diuretic hormone plasma level in healthy subjects function must be awaited, but here certainly is a and in patients with liver disease. Lee and fascinating field for future research. Bisset (1958) on the other hand were able to detect higher levels of antidiuretic hormone The Antidiuretic activity in blood from the internal jugular vein Hormone than in blood from the median cubital vein and Finally, brief mention must be made of the they found a distinct elevation of antidiuretic antidiuretic hormone (ADH) of the pituitary; its activity in blood from the internal jugular vein in significance in the development and maintenance 5 patients with cirrhosis and ascites. The signi- of ascites has not been clarified. Wolff and others, ficance of these findings awaits interpretation. REFERENCES ALSTED, G. (1947): Studies on Malignant Hepatitis, Amer. J. med. Sci., 213, 257. BARR, R. W., and SOMMERS, S. C. (1957): Endocrine Abnormalities Accompanying Hepatic Cirrhosis and Hepatoma, J. clin. Endocr., 17, 1017. BARTTER, F. C., Editor (1960): 'The Clinical Use of Aldosterone Antagonists'. Springfield, Illinois: Charles C Thomas. BEAN, W. B. 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