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ENHANCED OXYGEN TENSION IN THE LIVER AND SERUM-CHOLESTEROL-LOWERING EFFECT OF PORTACAVAL SHUNT IN HYPERLIPIDÆMIA
776 ENHANCED OXYGEN TENSION IN THE LIVER AND SERUM-CHOLESTEROL-LOWERING EFFECT OF PORTACAVAL SHUNT IN HYPERLIPIDÆMIA
SIR,-Starzl and his colleagues reported that a portacaval a patient with homozygous familial hypercholes-
shunt in
terolsemia lowered serum-cholesterol from 20 to 8 mmol/l.1-3 The reduced level persisted during the observed 18 months, except for two short periods of respiratory infections, when serum-cholesterol rose to 13 mmol/l. The lipid-lowering effect of portacaval shunt has now been confirmed by others, but the mechanism is still uncertain.4 Starzl himself proposed peripheral elimination of a pancreatic factor1 which would normally stimulate lipid synthesis in the liver. We want to draw your attention to oxygen tension in the liver as a possible factor in the regulation of cholesterol metabolism. After a portacaval shunt the oxygen tension in liver cells will increase owing to elimination of venous blood and a concomitant compensatory increase in the flow of highly oxygenated blood through the hepatic artery. A high oxygen tension in liver cells might then either decrease the synthesis or increase the catabolism of cholesterol. The reduction in serumcholesterol observed during intravenous hyperalimentation in normal and hypercholesterolaemic subjects5 6 might be 1.
Starzl, T. E., Putnam, C. W., Chase, H. P., Porter, K. A. Lancet 1973,
ii,
940.
explained along the same lines by absence of the usual increase in venous blood-flow to the liver during intestinal food digestion. This hypothesis is prompted by the following experimental findings. Cholesterol-fed rabbits breathing 10(% oxygen obtained a higher level of serum-cholesterol, and cholesterolfed rabbits breathing 35% oxygen a lower level, than cholesterol-fed control rabbits breathing atmospheric air.’H In a patient with hepatic carcinoma we observed that ligation of the hepatic artery, presumably leading to a fall in liver oxygen tension, was followed by a steady increase in serum-cholesterol from a preoperative level of 4 mmol/1 to a maximum value of 7 mmol/1 a month after the operation. When the patient was seen again at the hospital 6 months after the operation, Just before death, the serum-cholesterol had fallen to the preoperative level. The last decrease in serum-cholesterol might be ascribed to the development of alternative pathways for arterial blood to the liver, as verified on section. In Starzl’s patient serum-cholesterol rose during the two episodes of respiratory infection, which may have caused a reduced oxygen tension in arterial blood and hence also in the liver. Department of Clinical Chemistry A, Rigshospitalet,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Starzl, T. E., Chase, H. P., Putnam, C. W., Nora, J. J. ibid. 1974, ii, 714. Starzl, T. E., Chase, H. P., Putnam, C. W., Nora, J J., Fennell, R. H , Jr., Porter, K. A. ibid. p. 1263. 4. Stein, E. A., Mieny, C., Spitz, L., Saaron, I., Pettifor, J., Heimann, K W, Bersohn, I., Dinner, M. ibid. 1975, i, 832. 5. Torsvik, H., Fischer, J. E., Feldman, H. A., Lees, R. S. ibid. p. 601.
STEEN STENDER POUL ASTRUP FINN DAMGAARD-PEDERSEN
2. 3.
Obituary GORDON COVELL
Kt., C.LE., M.D. Lond., D.P.H., D.T.M.&H. Sir Gordon Covell, formerly director of the Indian Malaria Institute, died on Oct. 4 at the age of 87. He was educated at King’s School, Canterbury, and Guy’s
Hospital, graduating M.B. in 1913 and M.D. in 1923. A large part of his professional career was spent in the Indian Medical Service, and he was made a major-general in 1944. On his return to Britain following his retirement as director of the Indian Malaria Institute in 1947, he carried on with his work on malaria, becoming director of the Ministry of Health malaria laboratory at Horton Hospital, Epsom. He was appointed C.LE. in 1939 and was knighted in 1946; he was honorary physician to the King in 1944-47. His published work included the book, Malaria Control by Anti-Mosquito Measures, published in 1941.
P.C.C.G. writes: "Covell’s life-work was devoted to malaria. He first came into contact with the ravages of the disease during the campaigns of the 1914-18 war in German East Africa. When the war ended he went to India and became absorbed into the inspiring group of malariologists of the Indian Medical Service, which included Christophers, Sinton, and Shortt, and later Hugh Mulligan, Jaswant Singh, and Afridi. Together they formed the Malaria Survey (later Institute) of India, and probably Covell more than any was responsible for the meticulous surveys and control measures in the sub-continent. His work in the Andaman Islands, in Sind, and in the Bombay Presidency was particularly outstanding, and constitutes a practical illustration of the famous little book How to do a Malaria Survey by Christophers, Sinton, and Covell. The field rather than the laboratory was his home, and his chief use for the institute
6.
DenBesten, L., Reyna, R. H., Connor, W. E., Stegmk, L. D. J. clin. Invest 1973, 52, 1384. 7. Kjeldsen, K., Wanstrup, J , Astrup, P. J atheroscler. Res 1968, 8, 835 8. Kjeldsen, K., Astrup, P., Wanstrup, J. ibid. 1969, 10, 173
place both to plan from and to train a cadre of Indian workers to succeed him when the British were to leave India, The fruits of these plans and the calibre of his successors were the chief factors responsible for the nearly successful eradication of malaria from India a few years later. "On his return to England after the 1939-45 war, the second part of Covell’s career began: he became director of the Mott Malaria Therapy Unit at Horton Hospital, Epsom. In conjunction with P. G. Shute and workers at the London School of Hygiene and Tropical Medicine, he helped to unravel the last great problem in the life-cycle of human malaria parasites--i.e., the demonstration of the third or exoerythrocytic phase in the liver. Covell’s personality was just right for dealing with the delicate situations with which this work was beset; he was very much persona grata with the medical staff and was diplomatic enough always to get his own way-for instance, in obtaining permission to import from India and breed in the grounds of the hospital a dangerous mosquito vector of malaria (Anopheles stephensi). His kindness, transparent honesty, and high ethical principles were as invaluable here as they had been earlier in India. These characteristics were also greatly appreciated in the World Health Organisation, where his services were often sought and his advice taken, and which awarded him the Darling medal and prize. "Covell was excessively modest; he was astounded when in 1946 he received news of his knighthood, and quite overcome by the ovation which greeted his award of the Manson medal at Manson House in 1971. He played rugger for Guy’s and once played cricket with Grace, and he and his familv continued to excel in sport. Later in life his gaunt and haggard appearance was deceptive, and his younger companions on long and tiring trips in East Africa found it difficult to keep up with him; he loved these journeys in malarious countr which brought back early memories. He never became bedridden (he would not even sleep in a bed latterly) and onh siB weeks before his death he was still enjoying classical music and listened with interest to the latest progress of his science. He died, cherished by his wife, happy with his family, and admired by innumerable friends in every continent." was as a
.
SIR,-Starzl and his colleagues reported that a portacaval a patient with homozygous familial hypercholes-
shunt in
terolsemia lowered serum-cholesterol from 20 to 8 mmol/l.1-3 The reduced level persisted during the observed 18 months, except for two short periods of respiratory infections, when serum-cholesterol rose to 13 mmol/l. The lipid-lowering effect of portacaval shunt has now been confirmed by others, but the mechanism is still uncertain.4 Starzl himself proposed peripheral elimination of a pancreatic factor1 which would normally stimulate lipid synthesis in the liver. We want to draw your attention to oxygen tension in the liver as a possible factor in the regulation of cholesterol metabolism. After a portacaval shunt the oxygen tension in liver cells will increase owing to elimination of venous blood and a concomitant compensatory increase in the flow of highly oxygenated blood through the hepatic artery. A high oxygen tension in liver cells might then either decrease the synthesis or increase the catabolism of cholesterol. The reduction in serumcholesterol observed during intravenous hyperalimentation in normal and hypercholesterolaemic subjects5 6 might be 1.
Starzl, T. E., Putnam, C. W., Chase, H. P., Porter, K. A. Lancet 1973,
ii,
940.
explained along the same lines by absence of the usual increase in venous blood-flow to the liver during intestinal food digestion. This hypothesis is prompted by the following experimental findings. Cholesterol-fed rabbits breathing 10(% oxygen obtained a higher level of serum-cholesterol, and cholesterolfed rabbits breathing 35% oxygen a lower level, than cholesterol-fed control rabbits breathing atmospheric air.’H In a patient with hepatic carcinoma we observed that ligation of the hepatic artery, presumably leading to a fall in liver oxygen tension, was followed by a steady increase in serum-cholesterol from a preoperative level of 4 mmol/1 to a maximum value of 7 mmol/1 a month after the operation. When the patient was seen again at the hospital 6 months after the operation, Just before death, the serum-cholesterol had fallen to the preoperative level. The last decrease in serum-cholesterol might be ascribed to the development of alternative pathways for arterial blood to the liver, as verified on section. In Starzl’s patient serum-cholesterol rose during the two episodes of respiratory infection, which may have caused a reduced oxygen tension in arterial blood and hence also in the liver. Department of Clinical Chemistry A, Rigshospitalet,
Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Starzl, T. E., Chase, H. P., Putnam, C. W., Nora, J. J. ibid. 1974, ii, 714. Starzl, T. E., Chase, H. P., Putnam, C. W., Nora, J J., Fennell, R. H , Jr., Porter, K. A. ibid. p. 1263. 4. Stein, E. A., Mieny, C., Spitz, L., Saaron, I., Pettifor, J., Heimann, K W, Bersohn, I., Dinner, M. ibid. 1975, i, 832. 5. Torsvik, H., Fischer, J. E., Feldman, H. A., Lees, R. S. ibid. p. 601.
STEEN STENDER POUL ASTRUP FINN DAMGAARD-PEDERSEN
2. 3.
Obituary GORDON COVELL
Kt., C.LE., M.D. Lond., D.P.H., D.T.M.&H. Sir Gordon Covell, formerly director of the Indian Malaria Institute, died on Oct. 4 at the age of 87. He was educated at King’s School, Canterbury, and Guy’s
Hospital, graduating M.B. in 1913 and M.D. in 1923. A large part of his professional career was spent in the Indian Medical Service, and he was made a major-general in 1944. On his return to Britain following his retirement as director of the Indian Malaria Institute in 1947, he carried on with his work on malaria, becoming director of the Ministry of Health malaria laboratory at Horton Hospital, Epsom. He was appointed C.LE. in 1939 and was knighted in 1946; he was honorary physician to the King in 1944-47. His published work included the book, Malaria Control by Anti-Mosquito Measures, published in 1941.
P.C.C.G. writes: "Covell’s life-work was devoted to malaria. He first came into contact with the ravages of the disease during the campaigns of the 1914-18 war in German East Africa. When the war ended he went to India and became absorbed into the inspiring group of malariologists of the Indian Medical Service, which included Christophers, Sinton, and Shortt, and later Hugh Mulligan, Jaswant Singh, and Afridi. Together they formed the Malaria Survey (later Institute) of India, and probably Covell more than any was responsible for the meticulous surveys and control measures in the sub-continent. His work in the Andaman Islands, in Sind, and in the Bombay Presidency was particularly outstanding, and constitutes a practical illustration of the famous little book How to do a Malaria Survey by Christophers, Sinton, and Covell. The field rather than the laboratory was his home, and his chief use for the institute
6.
DenBesten, L., Reyna, R. H., Connor, W. E., Stegmk, L. D. J. clin. Invest 1973, 52, 1384. 7. Kjeldsen, K., Wanstrup, J , Astrup, P. J atheroscler. Res 1968, 8, 835 8. Kjeldsen, K., Astrup, P., Wanstrup, J. ibid. 1969, 10, 173
place both to plan from and to train a cadre of Indian workers to succeed him when the British were to leave India, The fruits of these plans and the calibre of his successors were the chief factors responsible for the nearly successful eradication of malaria from India a few years later. "On his return to England after the 1939-45 war, the second part of Covell’s career began: he became director of the Mott Malaria Therapy Unit at Horton Hospital, Epsom. In conjunction with P. G. Shute and workers at the London School of Hygiene and Tropical Medicine, he helped to unravel the last great problem in the life-cycle of human malaria parasites--i.e., the demonstration of the third or exoerythrocytic phase in the liver. Covell’s personality was just right for dealing with the delicate situations with which this work was beset; he was very much persona grata with the medical staff and was diplomatic enough always to get his own way-for instance, in obtaining permission to import from India and breed in the grounds of the hospital a dangerous mosquito vector of malaria (Anopheles stephensi). His kindness, transparent honesty, and high ethical principles were as invaluable here as they had been earlier in India. These characteristics were also greatly appreciated in the World Health Organisation, where his services were often sought and his advice taken, and which awarded him the Darling medal and prize. "Covell was excessively modest; he was astounded when in 1946 he received news of his knighthood, and quite overcome by the ovation which greeted his award of the Manson medal at Manson House in 1971. He played rugger for Guy’s and once played cricket with Grace, and he and his familv continued to excel in sport. Later in life his gaunt and haggard appearance was deceptive, and his younger companions on long and tiring trips in East Africa found it difficult to keep up with him; he loved these journeys in malarious countr which brought back early memories. He never became bedridden (he would not even sleep in a bed latterly) and onh siB weeks before his death he was still enjoying classical music and listened with interest to the latest progress of his science. He died, cherished by his wife, happy with his family, and admired by innumerable friends in every continent." was as a
.