Medical Hypotheses 6: 1117-1122, 1880

POSSIBLE ROLE OF PROSTAGLANDINS IN THE PATHOGENESIS OF CIRRHOSIS OF THE LIVER

U.N. DAS, Department of Genetics, Osmania University & Faculty of Medicine, Osmania General Hospital, Hyderabad, India (reprint requests to UND at faculty of medicine, Osmania General Hospital).

ABSTRACT

The ability of ethanol, copper, iron and viruses to alter prostaglandin (PG) metabolism may be responsible for their ability to induce cirrhosis of liver. PGs are known to regulate fibroblast proliferation, glyco- saminoglycan and collagen synthesis and participate in immune response and inflammation. Thus, the beneficial effect of colchicine in cirrhosis could be due to its ability to enhance thromboxane A2 synthesis and normalise PG levels.

INTRODUCTION

Cirrhosis is characterised by diffuse fine scarring due to collapse and fibrosis of the supporting reticulin net work, a fairly uniform loss of liver cells associated with fatty infiltration or active necrosis and small islands of preserved and regenerating parenchyma (1). Though in the majority the inciting agent(s) that induces cirrhosis is not known, ethanol, malnutrition and viruses have been implicated in some cases (1). But in hemochromatosis and Wilson's disease excess of iron and copper respectively are the inciting agents. Perhaps these known facts may give a clue to the pathogenesis of cirrhosis.

Fibroblast proliferation, collagen synthesis and PGs

Of several factors that are likely to be involved in the regulation of collagen and pivotal role 9

lycosaminoglycan synthesis, vitamin C seems to have a 2). Wotid healing and colla en synthesis are defective

in vitamin C deficiency disease, scurvy (3 . Recently it has been 3 demonstrated that in essential fatty acid deficient animals there may be defects in collagen synthesis and wound healing similar to scurvy (4) and in them this defect can be corrected by 1 series prostaglandins (PGs) (4). Further PGEl seems to have a regulatory role in collagen and glycosaminoglycan synthesis (5, Bl). This coupled with the fact that vitamin C enhances PGEl synthesis (6) suggests that some of the known actions of vitamin C are mediated by its effect of PGEl synthesis. Since PGEl can accelerate wound healing, collagen and glycosanimoglycan synthesis, it is likely that increased amounts of PGs may induce excess fibrous tissue formation. This assumption is supported by the observation that PGs In additil called a of very 11

can initiate cell proliferation in cultured mouse fibroblasts (7). on a number of the biological actions of PGEl follow what is 'bell shaped' dose response curve. This means that the $f;z;; ow and very high concentrations of PGEl are identical.

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effects on collagen are similar then it is to be expected that collagen formation will be reduced both by very low and very high levels of PGEl. Thus it is predicted that excess fibrosis will be associated with moderately reduced and increased PGEl levels and that both very low and very high PGEl concentrations will lead to defective connective tissue formation. Further excess PGs are known to induce cell lysis as observed by us in the unicellular organism Entamoeba histolytica (30) which may explain liver cell necrosis and cirrhosis.

PGs AND IMiUNNE RESPONSE

Excess PGs are known to inhibit lymphocyte response to specific and non-specific antigens (8,9). But for normal T lymphocyte function adequate physiological amounts of PGEl seem to be essential (10,ll). That is excess of 2 series PGs induce itnnunosuppression and a relative deficiency of PGEl can inhibit T lymphocyte function, whereas an excess of PGEl may deppress cell mediated imnune response (CMI) (31). In addition, suppressor Tccells are known to elaborate PGs which may explain deficient CM1 response in Hodgkin's disease (8,12). Apart from this PGs are now believed to regulate cell membrane fluidity (13) and hence an altered PG metabolism will not only induce abnormalities in immune response but may also modify the cell membrane in such a way that the cell may be recognised as non-self by the immune apparatus of the body. Further, normally there seems to be a balance struck between PGs and thromboxane A2 (TxA2) levels in the cells, thus excess PG synthesis occurs as TxA2 deficiency sets in or vice-versa (14). Since TxA2 is believed to bind to DNA, render it non-antigenic and protect DNA from mutagenic influences, whenever TxA2 level falls, auto-antibodies will be produced (14). Hence, in situations wherein there is excess PG synthesis (PGEl, PGEP and PGF alpha),possibly due to a defect in TxA2 synthesis,will lead to deppressed CM1 response, enhanced gamnaglobulin levels due to deficient suppressor T lymphocyte function, excess collagen and fibroblast proliferation and elaboration.of auto-antibodies.

CIRRHOSIS OF LIVER AND PROSTAGLANDINS - A HYPOTHESIS

Since PGs are involved in the regulation of collagen synthesis and fibroblast proliferation (2-6,7), modify immune res onse levels of TxA2 enhance auto-antibody production (14 P

(8-12)and low as discussed

above, it is proposed here that excess PGEP- and decreased PGEl synthesis in the liver may be the pathogenic mechanism of cirrhosis (5). It is possible that excess PGE2 leads to excess fibros tissue formation and a deficiency of PGEl could be responsible for defective T lymphocyte function and thus excess gammaglobulin formation (5). Since both TxA2 and PGEl seem to be involved in inhibition of the synthesis of other 2 series PGS,lack of TxA2 and PGEl will be associated with excess formation of other PGs such as PGEP and PGF2 alpha. Copper, iron, ethanol and viruses are known to enhance PG synthesis (15,16,17,14). Excess copper has been demonstrated in the liver cells of Indian childhood cirrhosis, primary biliary cirrhosis and Wilson's disease (1,18,19)

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whereas excess iron accumulates in cases of hemochromatosis (1) and in alcoholic and Laennee's cirrhosis (1). The excess copper and iron in the liver cells and the virus in cases of viral hepatitis will enhance PGE2 and decrease PGEl synthesis and thus leads to the onset of cirrhosis as detailed above,since liver has complete system for PG metabolism (29). The suggestion that the hepatitis virus enhances PGE2 and decreases PGEl formation is supported by the observation that the virus infection is associated with imnune suppression and that excess PGE2 and deficient PGEl formation leads to defective T lymphocyte function (9, 10).

The increased incidence of infections observed in cirrhosis (1) could be due to excess PGE2 and low PGEl levels since lymphocyte response to antigens is regulated by them (8,9,10). A diabetic type of glucose tolerance may occur in cirrhosis and is considered as a reflection of endogenous insulin resistance (1). It is known that PG levels are high in the blood of diabetics as compared to non-diabetic (20), suggesting that glucose tolerance abnormalities observed in cirrhosis could be due to excess PGE synthesis. Similarly the frequent occurence of carcinoma of liver in cirrhosis patients may also be due to excess PGs present in their liver cells, since excess PGs have been demonstrated to be present in cancer cells (14) and predispose to the development of malignant transformation (14, 13). In about 15 percent of patients with hemochromatosis congestive cardiac failure and cardiac arrhythmias may occur (1). It is now believed that excess PGs may decrease myocardial contractility and induce cardiac arrhythmias (21,22), which explains the frequent cardiac complications in hemochromatosis, which could be due to enhanced PG synthesis in the cardiac tissue due to iron deposition.

CONCLUSIONS

The concept proposed that excess PGEP and low PGEl synthesis in the liver due to deposition or presence of increased amounts of iron, ethanol or viruses explains several features and complications observed in cirrhosis. The cause for this excess iron or copper accumulation in the liver cells could be either a congenital or an acquired defect, which is yet to be clarified. Whatever may be the mechanism of excess copper or iron deposition in the liver, the hypothesis presented suggests a new approach to cirrhosis. Thus methods designed to normalise PG levels in the liver may be of benefit in cirrhosis. In fact recently it has been shown that colchicine known to enhance TxA2 synthesis oh action and thus normalise PG levels, is of benefit in cirrhosis (23). Similarly the demonstration that penicillamine could be of use in biliary cirrhosis (24) may be due to its chelating action on copper and also because of its ability to enhance PGEl and TxA2 formation (5,23).

Increased hepatic alkaline phosphatase activity due to colchicine (25) may also be due to its action on the PG-system, since we recently demonstrated that PGs have a modifying influence on this enzyme in leukocytes (26,27). Similarly the fibrinolytic and anti-phagocytic properties of colchicine can also be attributed to its effect on PG metabolism, as PGs are known to be involved in fibroblast proliferation and phagocytosis (7,28). In view of this, increased use of colchicine in cirrhosis is worthy of trial.

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in cirrhosis may be attempted. Similarly drugs such pencillin, penicillamine and dihomogamma linolenic acid may also be of use in cirrhosis since they enhance PGEl formation and depress PGEP synthesis (5) and thus nonnalise immune response and decrease fibrous tissue formation.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

Thomas Lament J, Isselbacher K 3. Cirrhosis, in Harrisons' principles of internal medicine. Eds Thorn G.W., Adams R D, Braun Wald E, Isselbacher K J and petersdorf R G McGraw-Hill- Kogakusha Ltd., Tokyo P 1604, 8th edition, 1977.

Cameron E, Pauling L, Leibovitz B. Assorbic acid and cancer: a review. Cancer Res. 39:663, 1970

Bricknell F, Prescott F. The vitamins in medicine. Grune and Stratton, New York, 1953

Frankel T L, Rivers J P W. The nutritional and metabolic impact of ganmnalinolenic acid on cats deprived of animal lipid. Br J Nutr 39:227, 1978

Cunnane S C, Manku M.S, Horrobin D F. The pinael and regulation of fibrosis:Pinealectomy as a model of primary biliary cirrhosis: roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes. Med Hypotheses 5:403, 1979

Manku,M S,Oka M, Horrobin D F. Differential regulation of the formation of prostaglandins and related products from arachidonic acid and from dihomogammalinolenic acid. II Effects of vitamin C, Prostaglandins Med 3:129, 1979

de Asna L J, Clingan D, Rudland P S. Initiation of cell proliferation in cultured mouse fibroblasts by prostaglandin F2 alpha. Proc Nat1 Acad Sci USA 72:2724, 1975

Das U N, Padma M C. Role of prostaglandins in human fertility. Prostaglandins Med 1:319, 1978

Das U N, Padma M C. Prostaglandins in lymphocyte transformation. J Assoc Physicians India 26:503, 1978

Zurier R B, Sayodoff D M, Torrey S B, Rothfield N F. Prostaglandin E treatment in NZB/NZW mice. Arthritis Rheum 20:723, 1977

Das U N. Accelerated rejection of skin allograft in mice by prostaglandin El. IRCS Med Sci 8: 253, 1980.

1120

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

Goodwin J S, Messner R P, Bankhurst A D, etal. Prostaglandin producing suppressor cells in Hodgkin's disease New Engl J Med 297:963, 1977

Das U N. Cell membrane fluidity and prostaglandins.Medical Hypotheses, in press

Horrobin D F, etal. A defect in thromboxane AZ synthesis may be a factor predisposing to cancer. Prostaglandins Med 1:175, 1978.

Margaret E E. Anti-inflamnatory drugs and copper.Lancet 2:1329, 1974

Rao G H R, Gerrard J M, Eaton J W, White J G. The role of iron in prostaglandin synthesis - Ferrous iron mediated oxidation of arachidonic acid. Prostaglandins Med 1:55, 1978

Manku M S, Oka M, Horrobin D F. Differential regulation of the formation of prostaglandins and related substances from arachidonic acid and dihomo-gamma linolenic acid. I effects of ethanol. Prostaglandins Med 3:119, 1979

Tanner M S, Portman B, Mewat A P, etal. Increased hepatic copper concentration in Indian childhood cirrhosis. Lancet 1:1203, 1979

Popper H, Goldfisher S, Strenlibb I, etal. Cytoplasmic copper and its toxic effects: studies in Indian childhood cirrhosis.Lancet 1:1209, 1979

Waitzman M B, Rudman D. Prostaglandins in blood of diabetic versus non-diabetic humans. Prostaglandins Med 1:131, 1978

Das U N. Cardiac Pacemaking, Cardiac glycosides, antiarrhythmic drugs and Prostaglandins. Speculations Sei Tech 2:381, 1979

Oas U N. Cardiac arrhythmicas, anti-arrhythmic drugs and prostaglandins J Ind Med Assoc 74: 23, 1980

Kershenobich D, Uribe M, Snarez G I, etal. Treatment of cirrhosis with colchicine. A double blind randomized trial. Gastroenterology 77:532, 1979

Epsvein 0, DeVilliers D, Jain S, etal. Reduction of immune complexes and immuno globulins induced by D-Pencillamine in primary biliary cirrhosis.New Engl J Med 300: 274, 1979.

Wilfred G. Colchicine increases hepatic alkaline phosphatase activity. Biochim Biophys Acta 500:209, 1977

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26. Das U N, Sandhya P. Enhancement of leukocyte alkaline phosphatase activity in chronic myeloid leukamia by cyclic AMP and chloroquine. IRCS Med Sci 7:535, 1979

27. Sandhya P, Das U N. Dose dependant effect of prostaglandin E2 on normal human leukocyte alkaline phosphatase activity.IRCS Med Sci 8:304, 1980.

28. Das U N.FeFever, leukocytes and prostag1andins.J Assoc Physicians J Assoc Physicians India 27:659, 1979

29. Wilson D E. Medical significance of prostaglandins.Arch Int Med 133:29, 1974

30. Das U.N. Unpublished data.

31. Horrobin DF. The regulation of prostaglandin biosynthesis: Negative feed back mechanisms and the selective control of formation of 1 and 2 series prostaglandins: Relevance to inflatnnation and immunity. Med Hypotheses 6: 687, 1980

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