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Some Endocrine Changes in Liver Disease G 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.
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