Hepatic Siderosis in Alcoholics ANDREW W. JAKOBOVITS, FRACP, MARSHA Y. MORGAN, MRCP, and SHEILA SHERLOCK, MD
In a population o f 157 (120 males, 37females) predominantly British alcoholics with liver disease, the incidence o f some degree o f hepatic siderosis, as estimated by stainable parenchymal iron, was 57.3%. The incidence o f significant siderosis (grades III and IV) was 7%, and was similar for both sexes. In the female alcoholics there was a significant correlation between age and the degree of siderosis (P < 0.05)--four o f the five females with significant siderosis being premenopausal. In the male alcoholics there was a significant inverse relationship between the grams o f ethanol consumed per day and the degree of siderosis (P < 0.05) and a significant correlation between the percentage saturation of iron-binding protein and the degree o f siderosis (P < 0.05). The mean daily iron intake from alcoholic beverages was 1.5 mg; there was no relationship between the amount o f iron ingested in the alcohol and the degree of siderosis. In this population o f alcoholics the incidence of significant siderosis in both sexes was low.
Difficulty is said to arise on occasions in distinguishing histologically b e t w e e n idiopathic hemochromatosis and alcoholic cirrhosis with secondary iron overload. Two factors are said to compound this difficulty. Firstly histologically stainable iron deposits are reported as common in cirrhotic livers especially in alcoholics (1), and secondly there is a high prevalence of alcoholism in patients with hemochromatosis, probably of the order of 25% (2-4). The iron overload seen in alcoholics has been variously ascribed to changes in iron absorption mediated by the ethanol itself (5) or to an increased intake of iron from the alcoholic beverages. Wine, particularly red wine, contains large amounts of iron (6), and many workers have explained the hepatic iron associated with heavy wine drinking on this basis (7-9). Barry (10), states that hepatic iron excess in British alcoholics is Unusual and ascribes this to their low wine consumption. In our experience, however, the difficulty of distinguishing between idiopathic hemochromatosis and alcoholic liver disease with secondary iron From the Department of Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, England Address for reprint requests: Dr. M.Y. Morgan, Department of Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, England
overload is rarely encountered, and indeed the percentage of alcoholics seen with histologically significant siderosis appears small. We have therefore surveyed a group of 157 alcoholics admitted consecutively to the Medical Unit at the Royal Free Hospital, London. The incidence and degree of hepatic siderosis, as estimated by stainable parenchymal iron, were determined and an attempt made to correlate the degree of siderosis with several factors that might be of importance in its etiology. MATERIALS AND METHODS
In the nine-month period January to September 1977, 157 patients (120 males, 37 females) were admitted to the Medical Unit of the Royal Free Hospital London with a history of alcohol abuse, defined as an intake of at least 50 g of ethanol a day for three or more years, and with disturbed liver function test results. Relevant personal details were documented, including in the females, a menstrual history. The age of onset of drinking, and of regular, heavy drinking, were recorded as far as possible, as were the amount and type of beverage consumed per day. The number of grams of ethanol taken per day was calculated, and the number of milligrams of iron ingested in the alcoholic beverage per day estimated using data from McCance and Widdowson's The Composition of Foods (11) (Table 1). Dietary histories were taken from
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979) 0163-2116/79/0400-0305503.00/1 9 1979 Digestive Disease Systems, Inc.
305
JAKOBOVITS ET AL TABLE 1. AVERAGEALCOHOL AND IRON CONTENT OF COMMON BEVERAGES*
Beverage Beers Ciders Wines; heavy (Port, Sherry) Tables wines, white Table wines, red Spirits, 70% proof
Alcohol (g/lO0 ml)
Iron (mg/lO0 ml)
2.2- 6.6 3.8-10.5
0.01-0.05 0.30-0.50
15.6-16.1 8.8-10.2 8.9-10.1 31.5
0.30-0.50 0.50-1.20 0.65-1.30 Trace
*Adapted from tables in McCance and Widdowson's The Composition of Foods.
all 157 patients using a recall method. The daily iron intake from food and from nonalcoholic beverages was estimated using data from the same publication. In 47 patients (33 males, five premenopausal females, and nine postmenopausal females) the serum iron was measured using bathophenanthroline (12) and the total ir0n-binding capaCity by an absorption method (13). The percentage saturation of iron-binding protein was then calculated for each of these patients. Percutaneous needle biopsy was performed in all 157 patients and the histological findings classified as fatty change only, alcoholic hepatitis, cirrhosis, or cirrhosis with alcoholic hepatitis. Patients with fatty change or alcoholic hepatitis were defined as having precirrhotic disease. The amount of parenchymal cell iron was assessed using Pefls' stain; grade 0 indicating absence of siderosis, while grades I-IV represented increasing degrees of iron deposition (14). The liver biopsies were assessed blindly by two independent experienced observers. The overall incidence of hepatic siderosis was calculated and an attempt made to correlate the degree of siderosis with features of the patients' personal details, drinking history, the percentage saturation of iron-binding protein and the liver histology. Data was analyzed using the 2 x 2 X~test and Fishers' exact probability test. In the 11 patients with significant siderosis, full histocompatibility typing, using a microcytotoxity technique, was performed together with hemoglobin electrophoresis.
RESULTS The incidence and degree of hepatic siderosis are shown in Table 2. The overall incidence of siderosis in the males (55.8%) did not differ statistically from that in the females (62.1%). The incidence of grades III and IV siderosis, taken to represent significant hepatic iron overload, was 7% (11/157) in the whole group and was similar for the males, 5% (6/120), and the females, 13.6% (5/37). The mean age of the 120 males, 50.6 years (range 23-69) was similar to that of the 37 females, 48.4 years (range 26-64). Nine females (24.3%) were premenopausal. In the female alcoholics, there was a significant correlation between the age of the patient, and the degree of hepatic siderosis (r = -0.38; P < 0.05) (Figure 1), which was not seen in the males. Four of the five females with grade III siderosis were premenopausal. The mean length of drinking history for the males, 24.2 years (range 3-50) did not differ statistically from that of the females, 16.9 years (range 440). There was no significant relationship between the degree of siderosis and the length of the drinking history. Although the mean daily intake of ethanol in the males, 259.3 g (range 40-830) was not statistically different from the females, 216.9 g (range 50-800), the types of beverages favored differed between the sexes (Table 3). Five of the males but none of the females drank wine exclusively, although a further 14 males (11.7%) and seven females (18.9%) drank wine daily in addition to other alcoholic beverages. Thus, in the whole group, 26 alcoholics (16.6%) consumed some wine per day, but in only five (3.2%), all male, was wine the only alcoholic beverage taken. In the male patients there appeared to be a relationship between the degree of siderosis and the number of grams of alcohol consumed per day (r = - 0.24; P < 0.05).
TABLE 2. HEPATIC SIDEROSIS IN 120 MALE AND 37 FEMALE ALCOHOLICS
Degree of Siderosis Patients Whole group (157) Males
Grade 0 No. (%)
Grade I No. (%)
Grade 11 No. (%)
Grade 111 No. (%)
Grade IV No. (%)
67 (42.7)
48 (30.6)
31 (19.7)
8 (5.1)
3 (1.9)
53 (44.2)
37 (30.8)
24 (20)
3 (2.5)
3 (2.5)
14 (37.8)
11 (29.7)
5 (13.6)
0
(120) Females (37)
306
7 (18.9)
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
HEPATIC SIDEROSIS IN ALCOHOLICS The mean daily iron intake from the alcoholic beverages in the males 1.46 mg (range 0-19.2) did not differ significantly from the females 1.63 mg (range 0-14.7). The mean daily intake of iron from this source in the five male wine drinkers, 10.9 mg (range 6.5-19.2) was significantly higher than for the rest of the group (P < 0.01). In neither sex was there any relationship between the degree of siderosis and the milligrams of iron consumed daily in the alcoholic beverages (Figure 2). The mean daily iron intake from food and nonalcoholic beverages in the males, 7.4 mg (range 2.612.1), did not differ significantly from the females, 6.7 mg (range 2.1-10.8). The mean daily iron intake from these sources in the five male wine drinkers, 7.2 mg (range 4.2-11.6), did not differ from the rest of the group. The percentage saturation of iron-binding protein was estimated in 47 patients. The normal range for our laboratory is 25-40%. In the 33 males, the mean value was 35.4% (range 8-96) compared with a m e a n of 24.2% (range 4-39) in the five premenopausal females and of 36.7% (range 14-67) in the nine postmenopausal females. The differences between these groups were not statistically significant. In males there was a significant relationship between the percentage saturation of iron-binding protein and the degree of hepatic siderosis (r = 0.41, P < 0.05), but this relationship just failed to reach statistical significance in the females (r = 0.48; 0.1 > P > 0.05). The histological findings on liver biopsy are shown in Table 4. Similar numbers of males 66/120 (55%) and females 17/37 (45.9%) had precirrhotic liver lesions. In males there tended to be a higher incidence of significant siderosis in the patients with cirrhosis 5/54 (9.3%) compared with the patients with precirrhotic lesions 1/66 (1.5%) (P = 0.086). In the females the incidence of significant siderosis was similar in the cirrhotic group 3/20 (15.0%) and in the precirrhotic group 2/17 (12.0%). There was no difference in the incidence of significant siderosis between the males and females.
70-
60-
"
""
50-
G,) cY
>- 40-
30-
O O o
O
0
2Q-
DEGREE OF SIDEROSIS Fig 1. Correlation in female alcoholics between the age of the patient in years and the degree of hepatic siderosis. Regression coetticient (r) = -0.38; P < 0.05. 9 represents postmenopausal females; o, premenopausal females.
In the 11 patients with significant siderosis there was no increase in the incidence of the A3 or B14 phenotypes when compared with a control population of British Caucasians (Table 5). All 11 of these patients had normal hemoglobin electrophoresis. DISCUSSION The presence of hepatic siderosis was considered for a long time to be abnormal. However, in 1968, Weinfeld et al (15) investigated a group of hematologically normal patients without liver disease and
TABLE 3. BEVERAGESFAVORED BY 120 MALE AND 37 FEMALE ALCOHOLICS
Males Females
Beer No. (%)
Spirit No. (%)
15 (12.5) 3 (8.1)
34 (28.3) 12(32.4)
Beer and spirit No. (%) 51 (42.5) 6(16.2)
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
Fortified wine (sherry and martini) No. (%)
Fortified wine and spirit No. (%)
Wine No. (%)
2 (1.7) 4(10.8)
3 (2.5) 9(24.3)
5 (4.2) 0
Mixed drinking No. (%) 10 (8.3) 3(8.1)
307
JAKOBOVITS
15
-19.
15
ET A L
>-
E >-
oo LW (_0 (-9 rY ill > LIJ DQ
U3 > LU ~Q
l0
I C) zE 0
U O z 0
0 r~ LL
i0
0 E~ L
_
A LU
b-
A LU
b-
(.B Z
G 2= Z 0 tY
Z 0
C12
II 0
I | II
IU
IV
IEGREE OF SIDEROSIS
0
I
II
Ig
N
DEGREE OF SIDEROSIS
Fig 2. (Left) Correlation between the amount of iron taken daily in alcoholic beverages and the degree of hepatic siderosis in males. (o) Males drinking wine exclusively. (Right) Correlation between the amount of iron taken daily in alcoholic beverages and the degree of hepatic siderosis in females. (o) Premenopausal females.
found stainable parenchymal cell iron in 78% of the males, 66% of the nonmenstruating females and in 14% of the menstruating females. In other series the reported incidences of stainable liver cell iron in "control" populations have varied from 17% in needle biopsies (16) to 55% in postmortem biopsy specimens (17). In patients with liver disease a significant correlation has been shown between the histochemical grading of siderosis and the chemical estimation of liver iron (14, 15, 18). However, the relationship is not clear-cut and an appreciable amount of overlap can occur. This probably reflects the fact that iron may be stored in the liver either as the water-soluble ferritin, which is not stainable by conventional techniques, or as the insoluble, stainable hemosiderin (19). While grades I and II siderosis can occur in "control" subjects, significant siderosis--grades IlI and IV--invariably indicates increased liver iron content (10). In our population of predominantly British, middle-aged alcoholics with liver disease of varying
308
severity, the incidence of some degree of hepatic siderosis was 57.3%. Overall the severity of the liver disease did not appear to be a determining factor as siderosis was present in 59% of the patients with precirrhotic liver disease and in 55% of patients with cirrhosis. Our results are in agreement with those of Lereboullet et al (8), who found stainable iron in 50% of alcoholics with precirrhotic liver disease and in 66% with alcoholic cirrhosis, and likewise with Scheuer et al (14), who showed grade I and II siderosis in 59% of 22 alcoholics with varying degrees of liver damage including cirrhosis. Lundvall et al (18) found stainable parenchymal cell iron in 61% of alcoholics with precirrhotic disease, but in another study, Lundvall and Weinfeld (20) showed, using the desferrioxamine excretion test, that iron stores were similar in precirrhotic alcoholics and control subjects. Significant siderosis was present in 7% of our patients. Overall, there was no relationship to the sex of the patient, but male cirrhotics tended to have a greater incidence of significant siderosis than males with precirrhotic liver lesions. Lundvall et al (18), Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
HEPATIC SIDEROSIS IN ALCOHOLICS TABLE 4. LIVER BIOPSY FINDINGS AMONG 120 MALE AND 37 FEMALE ALCOHOLICS
Liver histology
Patients
Fatty change No. (%)
Alcoholic hepatitis No, (%)
Cirrhosis No. (%)
Cirrhosis and hepatitis No. (%)
Whole group
53 (33.8)
30 (19.1)
45 (28.7)
29 (18.4)
46 (38.3)
20 (16.7)
37 (30.8)
17 (14.2)
7 (18.9)
10 (27.0)
8 (21.6)
12 (32.5 )
(157) Males (120) Female s (37)
in contrast, found grade III siderosis in 10% of their precirrhotic alcoholics, but also in 10% of their "control" group. The mean daily iron intake from alcohol was 1.5 mg which is small when compared with the mean daily iron intake from other sources of 7.2 mg. This low mean value for iron intake from alcohol reflects the low content of iron in British beer and in distilled spirits. Although 26 of our alcoholics (16.6%) drank some wine daily, only five (3.2%), all male, drank wine exclusively. The daily iron intake from alcoholic beverages was higher in this group, but none showed significant hepatic siderosis. In fact, overall, no relationship could be confirmed between the amount of iron in the alcoholic drinks and the degree of hepatic siderosis for either sex. This agrees with the findings of Miralles Garcia and de Castro del Pozo (21), who showed, that despite a mean intake of iron from red wine approximating to 23 mg/day and in the absence of overt gastrointestinal bleeding, there was no correlation between the iron ingested from alcohol and chemically estimated liver iron. Powell (22), however, in a postmortem study, with alcohol histories taken retrospectively from close relatives, found significant correlations between both the iron content of the alcohol ingested and the amount of alcohol ingested and hepatic iron concentration. We found no correlation between hepatic siderosis and length of drinking history, thus confirming the earlier findings of Lundvall et al (18). The negative correlation in men between the amount of alcohol consumed and the degree of siderosis is puzzling. It is possible that the patients with the highest alcohol intakes may suffer more occult blood loss from the gastrointestinal tract from gastritis or peptic ulceration and so in effect "venesect" themselves. More difficult to explain is the relationship in the Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
female alcoholics between age and hepatic siderosis. Of the 37 females studied, nine were premenopausal and four of these (mean age 35 years) had grade III siderosis. None was taking either the oral contraceptive pill which is known to increase serum iron and total iron-binding capacity (23) or oral iron. In our male patients we showed a positive correlation between the percentage saturation of ironbinding protein and the degree of siderosis. The percentage saturation of iron-binding protein is a poor indicator of the state of total body iron stores (24), so that no definite conclusions can be drawn from this. In the 11 patients with significant siderosis a specific attempt was made to determine the cause of the iron overload and to look for specific etiological factors. There was no evidence of hemoglobinopathy or other iron-loading anemia, no evidence of transfusion iron overload or of oral iron overload either from the diet or from the alcoholic beverages they consumed. In none was there a family history of hemochromatosis, and the incidences of the Az and B14 phenotypes, which are known to be associated with this disease, were normal (25). Six of the eleven patients were young women, five of whom were still menstruating, and while this does not exclude a diagnosis of hemochromatosis it makes it extremely unlikely. We feel that these 11 patients had alcoholic liver disease with secondary iron overload. In summary, we have shown an incidence of hepatic siderosis of all degrees in 57.3% of our patients with alcoholic liver disease, and of a significant degree in 7%. In the male patients the degree of hepatic siderosis tended to be greater in those with cirrhosis; it was positively related to the percentage saturation of iron-binding protein and inversely related to the amount of alcohol consumed. In the fe-
309
JAKOBOVITS TABLE 5. DISTRIBUTION OF HLA ANTIGENS IN 11 ALCOHOLICS WITH SIGNIFICANT HEPATIC SIDEROSIS Alcoholics with siderosis ( N = 11) HLA antigens
A
No.
%
Controls (N = 31) No.
%
23 71 13 3.3 19.4 6.5 3.3 13 3.3 9.7 6.5 13
1 2 3 10 11 28 W 23 W 24 W 25 W 26 W 29 W 30 / W31 J Blank
2 8 -1 3 1 1 1 1 1 1 1
18 72 -9 27 9 9 9 9 9 9 9
7 22 4 1 6 2 1 4 1 3 2 4
3
27
4
B 5 7 8 12 13 14 17 27 W 5 W 10 W 15 W 18 W 22 Blank
1 2 3 3
9 18 27 27
1
9
5 1 1 1 1 2
45.5 9 9 9 9 18
3 6 6 14 2 1 1 l 10 4 7 1 1 3
13 9.7 19.4 19.4 45 6.5 3.3 3.3 3.3 32.3 13 22.6 3.3 3.3 9.7
male patients the degree of hepatic siderosis was related to age--being greater in the younger women. In neither sex was any relationship determined between the degree of siderosis and the amount of iron consumed in the alcoholic beverages. In conclusion these findings bear out our clinical impression that the incidence of significant hepatic siderosis in alcoholics is low. The number of occasions in which difficulty should arise in distinguishing histologically b e t w e e n idiopathic hemochromatosis and alcoholic liver disease with secondary iron overload should be small. ACKNOWLEDGMENTS W e w i s h to t h a n k o u r D e p a r t m e n t o f D i e t e t i c s for valuable a d v i c e a n d help w i t h the d i e t a r y histories, P r o f e s s o r P e t e r S c h e u e r a n d c o w o r k e r s for i n t e r p r e t i n g the l i v e r b i o p s i e s , Miss O l y m p i a D e m e t r i o u for m e a s u r e m e n t o f the s e r u m iron a n d t o t a l i r o n - b i n d i n g c a p a c i t y , a n d Dr. R. B a t e y at T h e R o y a l F r e e H o s p i t a l for helpful d i s c u s s i o n . REFERENCES 1. Bell ET: Relation of portal cirrhosis to haemochromatosis and to diabetes mellitus. Diabetes 4:435-446, 1955
310
ET AL
2. Finch CS, Finch CA: Idiopathic haemochromatosis: An iron-storage disease. Medicine 34:381-430, 1955 3. MacDonald RA: Idiopathic haemochromatosis: Genetic or acquired? Ann Intern Med 112:184-193, 1963 4. Powell LW: Changing concepts in haemochromatosis. Postgrad Med J 46:200-209, 1970 5. Charlton RW, Jacobs P, Seftel H, Bothwell TH: Effect of alcohol on iron absorption. Br Med J 2:1427-1429, 1964 6. Perman G: Haemochromatosis and red wine. Acta Med Scand 182:281-284, 1967 7. Gilbert A, Gernet A: Cirrhose alcoolique hypertrophique pigmentaire. CR Acad Sci (Paris) 3:1078-1081, 1896 8. Lereboullet J, Levillain R, Debesse B: L'hepatosiderose. Sa frequence chez les alcooliques, etudes statistique de 350 examens anatomique. Bull Mere Soc Med Hop Paris 72:684689, 1956 9. Andr6 J: Le demembrement des hemachromatosis. Rev Int Hepatol 11:113-174, 1961 10. Barry M: Iron and chronic liver disease. J R Coll Physicians London 8:52-62, 1973 11. Paul AA, Southgate DAT (eds): McCance and Widdowson's The Composition of Foods, 4th ed. London, HMSO, 1978 12. International Committee for Standardination in Haematology Proposed recommendations for measurement of serum iron in human blood. J Clin Pathol 24:334-335, 1971 13. Cook JD: An evaluation of adsorption methods for measurement of plasma iron-binding capacity. J Lab Clin Med 76:497-506, 1970 14. Scheuer PJ, Williams R, Muir AR: Hepatic pathology in relatives of patients with idiopathic haemochromatosis. J Pathol Bateriol 84:53-64, 1962 15. Weinfeld A, Lundin P, Lundvall O: Significance for the diagnosis of iron overload of histochemical and chemical iron in the livers of control subjects. J Clin Pathol 21:35-40, 1968 16. Edwards CQ, Carroll M, Bray P, Cartwright GE: Hereditary haemochromatosis. Diagnosis in siblings and children. N Engl J Med 297:7-13, 1977 17. Pechet GS, French SW, Levy J, MacDonald RA: Histologic and chemical tissue iron. Arch Pathol 79:452-461, 1965 18. Lundvall O, Weinfeld A, Lundin P: Iron stores in alcohol abusers 1. Liver iron. Acta Med Scand 185:259-269, 1969 19. Barry M: Iron and the liver. Gut 15:324-334, 1974 20. Lundvall O, Weinfeld A: Iron stores in alcohol abusers 11. As measured with the desferrioxamine test. Acta Med Scand 185:271-277, 1969 21. Miralles Garcia JM, de Castro del Pozo S: Iron deposits in chronic alcoholics. Special studies in relation to the iron contained in red wine. Acta Hepatogastroenterol 23:10-19, 1976 22. Powell LW: Normal human iron storage and its relation to ethanol consumption. Australas Ann Med 15:110-115, 1966 23. Burton JL: Effect of oral contraceptives on haemoglobin, packed cell volume, serum iron and total iron-binding capacity in healthy women. Lancet 1:978-980, 1967 24. Beamish MR, Walker R, Miller F, Worwood M, Jacobs A, Williams R, Corrigall A: Transferrin iron, chelatable iron and ferritin in idiopathic haemochromatosis. Br J Haematol 27:219-228, 1974 25. Simon M, Barrel M, Fauchet R, Genetet B: Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17:332-334, 1976 Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
In a population o f 157 (120 males, 37females) predominantly British alcoholics with liver disease, the incidence o f some degree o f hepatic siderosis, as estimated by stainable parenchymal iron, was 57.3%. The incidence o f significant siderosis (grades III and IV) was 7%, and was similar for both sexes. In the female alcoholics there was a significant correlation between age and the degree of siderosis (P < 0.05)--four o f the five females with significant siderosis being premenopausal. In the male alcoholics there was a significant inverse relationship between the grams o f ethanol consumed per day and the degree of siderosis (P < 0.05) and a significant correlation between the percentage saturation of iron-binding protein and the degree o f siderosis (P < 0.05). The mean daily iron intake from alcoholic beverages was 1.5 mg; there was no relationship between the amount o f iron ingested in the alcohol and the degree of siderosis. In this population o f alcoholics the incidence of significant siderosis in both sexes was low.
Difficulty is said to arise on occasions in distinguishing histologically b e t w e e n idiopathic hemochromatosis and alcoholic cirrhosis with secondary iron overload. Two factors are said to compound this difficulty. Firstly histologically stainable iron deposits are reported as common in cirrhotic livers especially in alcoholics (1), and secondly there is a high prevalence of alcoholism in patients with hemochromatosis, probably of the order of 25% (2-4). The iron overload seen in alcoholics has been variously ascribed to changes in iron absorption mediated by the ethanol itself (5) or to an increased intake of iron from the alcoholic beverages. Wine, particularly red wine, contains large amounts of iron (6), and many workers have explained the hepatic iron associated with heavy wine drinking on this basis (7-9). Barry (10), states that hepatic iron excess in British alcoholics is Unusual and ascribes this to their low wine consumption. In our experience, however, the difficulty of distinguishing between idiopathic hemochromatosis and alcoholic liver disease with secondary iron From the Department of Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, England Address for reprint requests: Dr. M.Y. Morgan, Department of Medicine, Royal Free Hospital, Pond Street, Hampstead, London NW3 2QG, England
overload is rarely encountered, and indeed the percentage of alcoholics seen with histologically significant siderosis appears small. We have therefore surveyed a group of 157 alcoholics admitted consecutively to the Medical Unit at the Royal Free Hospital, London. The incidence and degree of hepatic siderosis, as estimated by stainable parenchymal iron, were determined and an attempt made to correlate the degree of siderosis with several factors that might be of importance in its etiology. MATERIALS AND METHODS
In the nine-month period January to September 1977, 157 patients (120 males, 37 females) were admitted to the Medical Unit of the Royal Free Hospital London with a history of alcohol abuse, defined as an intake of at least 50 g of ethanol a day for three or more years, and with disturbed liver function test results. Relevant personal details were documented, including in the females, a menstrual history. The age of onset of drinking, and of regular, heavy drinking, were recorded as far as possible, as were the amount and type of beverage consumed per day. The number of grams of ethanol taken per day was calculated, and the number of milligrams of iron ingested in the alcoholic beverage per day estimated using data from McCance and Widdowson's The Composition of Foods (11) (Table 1). Dietary histories were taken from
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979) 0163-2116/79/0400-0305503.00/1 9 1979 Digestive Disease Systems, Inc.
305
JAKOBOVITS ET AL TABLE 1. AVERAGEALCOHOL AND IRON CONTENT OF COMMON BEVERAGES*
Beverage Beers Ciders Wines; heavy (Port, Sherry) Tables wines, white Table wines, red Spirits, 70% proof
Alcohol (g/lO0 ml)
Iron (mg/lO0 ml)
2.2- 6.6 3.8-10.5
0.01-0.05 0.30-0.50
15.6-16.1 8.8-10.2 8.9-10.1 31.5
0.30-0.50 0.50-1.20 0.65-1.30 Trace
*Adapted from tables in McCance and Widdowson's The Composition of Foods.
all 157 patients using a recall method. The daily iron intake from food and from nonalcoholic beverages was estimated using data from the same publication. In 47 patients (33 males, five premenopausal females, and nine postmenopausal females) the serum iron was measured using bathophenanthroline (12) and the total ir0n-binding capaCity by an absorption method (13). The percentage saturation of iron-binding protein was then calculated for each of these patients. Percutaneous needle biopsy was performed in all 157 patients and the histological findings classified as fatty change only, alcoholic hepatitis, cirrhosis, or cirrhosis with alcoholic hepatitis. Patients with fatty change or alcoholic hepatitis were defined as having precirrhotic disease. The amount of parenchymal cell iron was assessed using Pefls' stain; grade 0 indicating absence of siderosis, while grades I-IV represented increasing degrees of iron deposition (14). The liver biopsies were assessed blindly by two independent experienced observers. The overall incidence of hepatic siderosis was calculated and an attempt made to correlate the degree of siderosis with features of the patients' personal details, drinking history, the percentage saturation of iron-binding protein and the liver histology. Data was analyzed using the 2 x 2 X~test and Fishers' exact probability test. In the 11 patients with significant siderosis, full histocompatibility typing, using a microcytotoxity technique, was performed together with hemoglobin electrophoresis.
RESULTS The incidence and degree of hepatic siderosis are shown in Table 2. The overall incidence of siderosis in the males (55.8%) did not differ statistically from that in the females (62.1%). The incidence of grades III and IV siderosis, taken to represent significant hepatic iron overload, was 7% (11/157) in the whole group and was similar for the males, 5% (6/120), and the females, 13.6% (5/37). The mean age of the 120 males, 50.6 years (range 23-69) was similar to that of the 37 females, 48.4 years (range 26-64). Nine females (24.3%) were premenopausal. In the female alcoholics, there was a significant correlation between the age of the patient, and the degree of hepatic siderosis (r = -0.38; P < 0.05) (Figure 1), which was not seen in the males. Four of the five females with grade III siderosis were premenopausal. The mean length of drinking history for the males, 24.2 years (range 3-50) did not differ statistically from that of the females, 16.9 years (range 440). There was no significant relationship between the degree of siderosis and the length of the drinking history. Although the mean daily intake of ethanol in the males, 259.3 g (range 40-830) was not statistically different from the females, 216.9 g (range 50-800), the types of beverages favored differed between the sexes (Table 3). Five of the males but none of the females drank wine exclusively, although a further 14 males (11.7%) and seven females (18.9%) drank wine daily in addition to other alcoholic beverages. Thus, in the whole group, 26 alcoholics (16.6%) consumed some wine per day, but in only five (3.2%), all male, was wine the only alcoholic beverage taken. In the male patients there appeared to be a relationship between the degree of siderosis and the number of grams of alcohol consumed per day (r = - 0.24; P < 0.05).
TABLE 2. HEPATIC SIDEROSIS IN 120 MALE AND 37 FEMALE ALCOHOLICS
Degree of Siderosis Patients Whole group (157) Males
Grade 0 No. (%)
Grade I No. (%)
Grade 11 No. (%)
Grade 111 No. (%)
Grade IV No. (%)
67 (42.7)
48 (30.6)
31 (19.7)
8 (5.1)
3 (1.9)
53 (44.2)
37 (30.8)
24 (20)
3 (2.5)
3 (2.5)
14 (37.8)
11 (29.7)
5 (13.6)
0
(120) Females (37)
306
7 (18.9)
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
HEPATIC SIDEROSIS IN ALCOHOLICS The mean daily iron intake from the alcoholic beverages in the males 1.46 mg (range 0-19.2) did not differ significantly from the females 1.63 mg (range 0-14.7). The mean daily intake of iron from this source in the five male wine drinkers, 10.9 mg (range 6.5-19.2) was significantly higher than for the rest of the group (P < 0.01). In neither sex was there any relationship between the degree of siderosis and the milligrams of iron consumed daily in the alcoholic beverages (Figure 2). The mean daily iron intake from food and nonalcoholic beverages in the males, 7.4 mg (range 2.612.1), did not differ significantly from the females, 6.7 mg (range 2.1-10.8). The mean daily iron intake from these sources in the five male wine drinkers, 7.2 mg (range 4.2-11.6), did not differ from the rest of the group. The percentage saturation of iron-binding protein was estimated in 47 patients. The normal range for our laboratory is 25-40%. In the 33 males, the mean value was 35.4% (range 8-96) compared with a m e a n of 24.2% (range 4-39) in the five premenopausal females and of 36.7% (range 14-67) in the nine postmenopausal females. The differences between these groups were not statistically significant. In males there was a significant relationship between the percentage saturation of iron-binding protein and the degree of hepatic siderosis (r = 0.41, P < 0.05), but this relationship just failed to reach statistical significance in the females (r = 0.48; 0.1 > P > 0.05). The histological findings on liver biopsy are shown in Table 4. Similar numbers of males 66/120 (55%) and females 17/37 (45.9%) had precirrhotic liver lesions. In males there tended to be a higher incidence of significant siderosis in the patients with cirrhosis 5/54 (9.3%) compared with the patients with precirrhotic lesions 1/66 (1.5%) (P = 0.086). In the females the incidence of significant siderosis was similar in the cirrhotic group 3/20 (15.0%) and in the precirrhotic group 2/17 (12.0%). There was no difference in the incidence of significant siderosis between the males and females.
70-
60-
"
""
50-
G,) cY
>- 40-
30-
O O o
O
0
2Q-
DEGREE OF SIDEROSIS Fig 1. Correlation in female alcoholics between the age of the patient in years and the degree of hepatic siderosis. Regression coetticient (r) = -0.38; P < 0.05. 9 represents postmenopausal females; o, premenopausal females.
In the 11 patients with significant siderosis there was no increase in the incidence of the A3 or B14 phenotypes when compared with a control population of British Caucasians (Table 5). All 11 of these patients had normal hemoglobin electrophoresis. DISCUSSION The presence of hepatic siderosis was considered for a long time to be abnormal. However, in 1968, Weinfeld et al (15) investigated a group of hematologically normal patients without liver disease and
TABLE 3. BEVERAGESFAVORED BY 120 MALE AND 37 FEMALE ALCOHOLICS
Males Females
Beer No. (%)
Spirit No. (%)
15 (12.5) 3 (8.1)
34 (28.3) 12(32.4)
Beer and spirit No. (%) 51 (42.5) 6(16.2)
Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
Fortified wine (sherry and martini) No. (%)
Fortified wine and spirit No. (%)
Wine No. (%)
2 (1.7) 4(10.8)
3 (2.5) 9(24.3)
5 (4.2) 0
Mixed drinking No. (%) 10 (8.3) 3(8.1)
307
JAKOBOVITS
15
-19.
15
ET A L
>-
E >-
oo LW (_0 (-9 rY ill > LIJ DQ
U3 > LU ~Q
l0
I C) zE 0
U O z 0
0 r~ LL
i0
0 E~ L
_
A LU
b-
A LU
b-
(.B Z
G 2= Z 0 tY
Z 0
C12
II 0
I | II
IU
IV
IEGREE OF SIDEROSIS
0
I
II
Ig
N
DEGREE OF SIDEROSIS
Fig 2. (Left) Correlation between the amount of iron taken daily in alcoholic beverages and the degree of hepatic siderosis in males. (o) Males drinking wine exclusively. (Right) Correlation between the amount of iron taken daily in alcoholic beverages and the degree of hepatic siderosis in females. (o) Premenopausal females.
found stainable parenchymal cell iron in 78% of the males, 66% of the nonmenstruating females and in 14% of the menstruating females. In other series the reported incidences of stainable liver cell iron in "control" populations have varied from 17% in needle biopsies (16) to 55% in postmortem biopsy specimens (17). In patients with liver disease a significant correlation has been shown between the histochemical grading of siderosis and the chemical estimation of liver iron (14, 15, 18). However, the relationship is not clear-cut and an appreciable amount of overlap can occur. This probably reflects the fact that iron may be stored in the liver either as the water-soluble ferritin, which is not stainable by conventional techniques, or as the insoluble, stainable hemosiderin (19). While grades I and II siderosis can occur in "control" subjects, significant siderosis--grades IlI and IV--invariably indicates increased liver iron content (10). In our population of predominantly British, middle-aged alcoholics with liver disease of varying
308
severity, the incidence of some degree of hepatic siderosis was 57.3%. Overall the severity of the liver disease did not appear to be a determining factor as siderosis was present in 59% of the patients with precirrhotic liver disease and in 55% of patients with cirrhosis. Our results are in agreement with those of Lereboullet et al (8), who found stainable iron in 50% of alcoholics with precirrhotic liver disease and in 66% with alcoholic cirrhosis, and likewise with Scheuer et al (14), who showed grade I and II siderosis in 59% of 22 alcoholics with varying degrees of liver damage including cirrhosis. Lundvall et al (18) found stainable parenchymal cell iron in 61% of alcoholics with precirrhotic disease, but in another study, Lundvall and Weinfeld (20) showed, using the desferrioxamine excretion test, that iron stores were similar in precirrhotic alcoholics and control subjects. Significant siderosis was present in 7% of our patients. Overall, there was no relationship to the sex of the patient, but male cirrhotics tended to have a greater incidence of significant siderosis than males with precirrhotic liver lesions. Lundvall et al (18), Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
HEPATIC SIDEROSIS IN ALCOHOLICS TABLE 4. LIVER BIOPSY FINDINGS AMONG 120 MALE AND 37 FEMALE ALCOHOLICS
Liver histology
Patients
Fatty change No. (%)
Alcoholic hepatitis No, (%)
Cirrhosis No. (%)
Cirrhosis and hepatitis No. (%)
Whole group
53 (33.8)
30 (19.1)
45 (28.7)
29 (18.4)
46 (38.3)
20 (16.7)
37 (30.8)
17 (14.2)
7 (18.9)
10 (27.0)
8 (21.6)
12 (32.5 )
(157) Males (120) Female s (37)
in contrast, found grade III siderosis in 10% of their precirrhotic alcoholics, but also in 10% of their "control" group. The mean daily iron intake from alcohol was 1.5 mg which is small when compared with the mean daily iron intake from other sources of 7.2 mg. This low mean value for iron intake from alcohol reflects the low content of iron in British beer and in distilled spirits. Although 26 of our alcoholics (16.6%) drank some wine daily, only five (3.2%), all male, drank wine exclusively. The daily iron intake from alcoholic beverages was higher in this group, but none showed significant hepatic siderosis. In fact, overall, no relationship could be confirmed between the amount of iron in the alcoholic drinks and the degree of hepatic siderosis for either sex. This agrees with the findings of Miralles Garcia and de Castro del Pozo (21), who showed, that despite a mean intake of iron from red wine approximating to 23 mg/day and in the absence of overt gastrointestinal bleeding, there was no correlation between the iron ingested from alcohol and chemically estimated liver iron. Powell (22), however, in a postmortem study, with alcohol histories taken retrospectively from close relatives, found significant correlations between both the iron content of the alcohol ingested and the amount of alcohol ingested and hepatic iron concentration. We found no correlation between hepatic siderosis and length of drinking history, thus confirming the earlier findings of Lundvall et al (18). The negative correlation in men between the amount of alcohol consumed and the degree of siderosis is puzzling. It is possible that the patients with the highest alcohol intakes may suffer more occult blood loss from the gastrointestinal tract from gastritis or peptic ulceration and so in effect "venesect" themselves. More difficult to explain is the relationship in the Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
female alcoholics between age and hepatic siderosis. Of the 37 females studied, nine were premenopausal and four of these (mean age 35 years) had grade III siderosis. None was taking either the oral contraceptive pill which is known to increase serum iron and total iron-binding capacity (23) or oral iron. In our male patients we showed a positive correlation between the percentage saturation of ironbinding protein and the degree of siderosis. The percentage saturation of iron-binding protein is a poor indicator of the state of total body iron stores (24), so that no definite conclusions can be drawn from this. In the 11 patients with significant siderosis a specific attempt was made to determine the cause of the iron overload and to look for specific etiological factors. There was no evidence of hemoglobinopathy or other iron-loading anemia, no evidence of transfusion iron overload or of oral iron overload either from the diet or from the alcoholic beverages they consumed. In none was there a family history of hemochromatosis, and the incidences of the Az and B14 phenotypes, which are known to be associated with this disease, were normal (25). Six of the eleven patients were young women, five of whom were still menstruating, and while this does not exclude a diagnosis of hemochromatosis it makes it extremely unlikely. We feel that these 11 patients had alcoholic liver disease with secondary iron overload. In summary, we have shown an incidence of hepatic siderosis of all degrees in 57.3% of our patients with alcoholic liver disease, and of a significant degree in 7%. In the male patients the degree of hepatic siderosis tended to be greater in those with cirrhosis; it was positively related to the percentage saturation of iron-binding protein and inversely related to the amount of alcohol consumed. In the fe-
309
JAKOBOVITS TABLE 5. DISTRIBUTION OF HLA ANTIGENS IN 11 ALCOHOLICS WITH SIGNIFICANT HEPATIC SIDEROSIS Alcoholics with siderosis ( N = 11) HLA antigens
A
No.
%
Controls (N = 31) No.
%
23 71 13 3.3 19.4 6.5 3.3 13 3.3 9.7 6.5 13
1 2 3 10 11 28 W 23 W 24 W 25 W 26 W 29 W 30 / W31 J Blank
2 8 -1 3 1 1 1 1 1 1 1
18 72 -9 27 9 9 9 9 9 9 9
7 22 4 1 6 2 1 4 1 3 2 4
3
27
4
B 5 7 8 12 13 14 17 27 W 5 W 10 W 15 W 18 W 22 Blank
1 2 3 3
9 18 27 27
1
9
5 1 1 1 1 2
45.5 9 9 9 9 18
3 6 6 14 2 1 1 l 10 4 7 1 1 3
13 9.7 19.4 19.4 45 6.5 3.3 3.3 3.3 32.3 13 22.6 3.3 3.3 9.7
male patients the degree of hepatic siderosis was related to age--being greater in the younger women. In neither sex was any relationship determined between the degree of siderosis and the amount of iron consumed in the alcoholic beverages. In conclusion these findings bear out our clinical impression that the incidence of significant hepatic siderosis in alcoholics is low. The number of occasions in which difficulty should arise in distinguishing histologically b e t w e e n idiopathic hemochromatosis and alcoholic liver disease with secondary iron overload should be small. ACKNOWLEDGMENTS W e w i s h to t h a n k o u r D e p a r t m e n t o f D i e t e t i c s for valuable a d v i c e a n d help w i t h the d i e t a r y histories, P r o f e s s o r P e t e r S c h e u e r a n d c o w o r k e r s for i n t e r p r e t i n g the l i v e r b i o p s i e s , Miss O l y m p i a D e m e t r i o u for m e a s u r e m e n t o f the s e r u m iron a n d t o t a l i r o n - b i n d i n g c a p a c i t y , a n d Dr. R. B a t e y at T h e R o y a l F r e e H o s p i t a l for helpful d i s c u s s i o n . REFERENCES 1. Bell ET: Relation of portal cirrhosis to haemochromatosis and to diabetes mellitus. Diabetes 4:435-446, 1955
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ET AL
2. Finch CS, Finch CA: Idiopathic haemochromatosis: An iron-storage disease. Medicine 34:381-430, 1955 3. MacDonald RA: Idiopathic haemochromatosis: Genetic or acquired? Ann Intern Med 112:184-193, 1963 4. Powell LW: Changing concepts in haemochromatosis. Postgrad Med J 46:200-209, 1970 5. Charlton RW, Jacobs P, Seftel H, Bothwell TH: Effect of alcohol on iron absorption. Br Med J 2:1427-1429, 1964 6. Perman G: Haemochromatosis and red wine. Acta Med Scand 182:281-284, 1967 7. Gilbert A, Gernet A: Cirrhose alcoolique hypertrophique pigmentaire. CR Acad Sci (Paris) 3:1078-1081, 1896 8. Lereboullet J, Levillain R, Debesse B: L'hepatosiderose. Sa frequence chez les alcooliques, etudes statistique de 350 examens anatomique. Bull Mere Soc Med Hop Paris 72:684689, 1956 9. Andr6 J: Le demembrement des hemachromatosis. Rev Int Hepatol 11:113-174, 1961 10. Barry M: Iron and chronic liver disease. J R Coll Physicians London 8:52-62, 1973 11. Paul AA, Southgate DAT (eds): McCance and Widdowson's The Composition of Foods, 4th ed. London, HMSO, 1978 12. International Committee for Standardination in Haematology Proposed recommendations for measurement of serum iron in human blood. J Clin Pathol 24:334-335, 1971 13. Cook JD: An evaluation of adsorption methods for measurement of plasma iron-binding capacity. J Lab Clin Med 76:497-506, 1970 14. Scheuer PJ, Williams R, Muir AR: Hepatic pathology in relatives of patients with idiopathic haemochromatosis. J Pathol Bateriol 84:53-64, 1962 15. Weinfeld A, Lundin P, Lundvall O: Significance for the diagnosis of iron overload of histochemical and chemical iron in the livers of control subjects. J Clin Pathol 21:35-40, 1968 16. Edwards CQ, Carroll M, Bray P, Cartwright GE: Hereditary haemochromatosis. Diagnosis in siblings and children. N Engl J Med 297:7-13, 1977 17. Pechet GS, French SW, Levy J, MacDonald RA: Histologic and chemical tissue iron. Arch Pathol 79:452-461, 1965 18. Lundvall O, Weinfeld A, Lundin P: Iron stores in alcohol abusers 1. Liver iron. Acta Med Scand 185:259-269, 1969 19. Barry M: Iron and the liver. Gut 15:324-334, 1974 20. Lundvall O, Weinfeld A: Iron stores in alcohol abusers 11. As measured with the desferrioxamine test. Acta Med Scand 185:271-277, 1969 21. Miralles Garcia JM, de Castro del Pozo S: Iron deposits in chronic alcoholics. Special studies in relation to the iron contained in red wine. Acta Hepatogastroenterol 23:10-19, 1976 22. Powell LW: Normal human iron storage and its relation to ethanol consumption. Australas Ann Med 15:110-115, 1966 23. Burton JL: Effect of oral contraceptives on haemoglobin, packed cell volume, serum iron and total iron-binding capacity in healthy women. Lancet 1:978-980, 1967 24. Beamish MR, Walker R, Miller F, Worwood M, Jacobs A, Williams R, Corrigall A: Transferrin iron, chelatable iron and ferritin in idiopathic haemochromatosis. Br J Haematol 27:219-228, 1974 25. Simon M, Barrel M, Fauchet R, Genetet B: Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 17:332-334, 1976 Digestive Diseases and Sciences, Vol. 24, No. 4 (April 1979)
