Portal hepatotrophic factors, diabetes mellitus and acute liver atrophy, hypertrophy and regeneration

Abstract

The acute influence of portal blood hepatotrophyic factors upon the canine liver and upon hepatic regeneration was studied after surgical operations which provided qualitatively different portal venous perfusion to the right and left liver lobes. With one such procedure called splanchnic division, the nutrient rich venous return from the intestines was directed to the left lobes, whereas the hormone rich blood from the pancreas and other splanchnic organs of the upper part of the abdomen passed to the right lobes. Within three to five days, the rate of cell division on both liver sides was increased as judged by autoradiography, but the hormone influenced right lobes exhibited hypertrophy and hyperplasia relative to the nutrient enriched left lobes. In the latter, the hepatocytes underwent pronounced atrophy, deglycogenation, depletion or distortion of the rough endoplasmic reticulum, fatty vacuolization and other structural changes. When 30 or 60 per cent hepatic resection was carried out at the same time as splanchnic division, the regeneration of the hormone dominated hepatic tissue after three to five days was greater than that of the hepatic tissue receiving the intestinal venous effluent, as judged by multiple criteria, although both liver sides participated in the regeneration process. The advantage enjoyed by the right liver lobes in relation to the left liver lobes both in the resting or in the regeneration state after splanchnic division was reduced or eliminated by pre-existing alloxan-induced diabetes or after concomitant total pancreatectomy. Similar, but less complete, observations about the effect of pancreatectomy were made in dogs submitted to the procedure of partial portacaval transposition, in which all the splanchnic venous blood passed to the right lobes, whereas the left lobes were revascularized with systemic venous blood from the vena cava. These observations have added to the recent torrent of evidence that insulin is the most easily demonstrable and, therefore, probably the most important specific hepatotrophic factor in portal venous blood. At the same time, further subtle support has been added to our previously proposed hypothesis that mutliple other hormonal and possibly nonhormonal factors from the splanchnic viscera and other sources also contribute to the essence of the hepatotrophic effects. These effects were evident and quite advanced within a few days. A prominent hepatotrophic role of glucagon was not identifiable.

Fig. 1

A series of control procedures not involving partial hepatectomy. The dogs either were normal or had been submitted to acute splanchnic division, a, Group 1—normal dogs, with or without sham operation. b, Group 2—dogs in which the left liver lobes were perfused with intestinal blood and in which the right liver lobes received pancreaticogastroduodenosplenic venous blood. Explanation of partial removal of inferior lobe of pancreas is given in text. c, Group 3—same operation as in b, but in dogs with alloxan-induced diabetes. d, Group 4—same operation as in b, but with total pancreatectomy. The duodenum and common duct were left intact.

Fig. 2

Procedures involving hepatectomy or acute splanchnic division. a, Groups 5 and 6— hepatectomy without splanchnic division. The extent of hepatectomy was 30 per cent in group 5 and 60 per cent in group 6. b, Groups 7 and 8—splanchnic division was carried out plus 30 per cent, group 7, or 60 per cent, group 8, hepatectomy. c, Group 9—splanchnic division, total pancreatectomy and 30 per cent hepatectomy on the same day.

Fig. 3

Procedures involving acute partial portacaval transposition without partial hepatectomy. a, Group 10— partial portacaval transposition with systemic venous blood to left lobes. b, Group 11—same as in a, plus total pancreatectomy.

Fig. 4

Chronic partial portacaval. transposition plus delayed hepatectomy. a, Group 12—30 per cent hepatectomy three months after transpositon. b, Group 13—30 per cent hepatectomy and total pancreatectomy three months after transposition.

Fig. 5

Tritiated thymidine uptake expressed as specific activity in the right, R, and left, L, liver lobes of normal dogs with and without hepatic resections. Two doses of [CH³-₃H] thymidine were used. Five of the normal dogs from group 1 received 1.5 millicuries; the other six were given 4.5 millicuries. The four dogs of group 5 had 30 per cent liver resections; four days later, they received the smaller thymidine dose, Another four dogs, group 6, were sacrificed three days after 60 per cent resection; they received the larger thymidine dose. Note that 30 per cent resection caused only a slight increase in thymidine uptake, whereas the 60 per cent resection produced a sixfold increase in specific activity. N, Number of experiments.

Fig. 6

Relative thymidine uptake of the right, R, and left, L, liver lobes after splanchnic division. In each experiment, the liver lobe side having the greater specific activity was assigned a value of 100 per cent and a proportionally lower percentage calculated for the other side of the liver. The numbers in parentheses correspond to the dog groups described in the section on methods. Statistical comparisons between the right and left lobes in each group are indicated by p values or by NS, not significant. For comparison, the results are given in the top row from the normal dogs of group 1 and the dogs of groups 5 and 6 after hepatic resection. Note that the advantage in thymidine uptake enjoyed by the right lobes which received pancreaticogastroduodenosplenic blood after splanchnic division in groups 2, 7 and 8 was abolished in groups 3 and 4 or even transferred to the left lobes in group 9 by the creation of diabetes, either with alloxan or by pancreatectomy.

Fig. 7

Changes in a liver three days after a splanchnic division experiment of group 2 as shown by light microscopy, electron microscopy and autoradiography. The hepatocytes in the nutrient enriched lobes, panels on right, are atrophic; depleted of glycogen and rough endoplasmic reticulum and contain increased smooth endoplasmic reticulum when compared with the enlarged and ultrastructurally normal liver cells in the hormone influenced lobes, panels on left. The rate of cell division, as indicated by autoradiography, is increased on both sides of the liver, but particularly in the hormone influenced lobes. Upper panels, hematoxylin and eosin, ×120; middle panels, electron micrography, ×1,700; and lower panels, autoradiography, ×300.

Fig. 8

Changes in a liver three days after a splanchnic division and total pancreatectomy experiment of group 4B as shown by light microscopy, electron microscopy and autoradiography. The hepatocytes on both sides of the liver are atrophic and contain excess cytoplasmic fat. The amount of glycogen and rough endoplasmic reticulum is reduced: The rate of cell division, as indicated by autoradiography, is bilaterally normal. Upper panels, hematoxylin and eosin, ×120; middle panels, electron micrography, ×1,700; and lower panels, autoradiography, ×300.

Fig. 9

Changes in a liver three days after a splanchnic division and 60 per cent hepatectomy experiment of group 8 as shown by light microscopy, electron microscopy and autoradiography. The hepatocytes on both sides of the liver are enlarged and contain normal amounts of rough endoplasmic reticulum, increased numbers of autophagosomes and lipid droplets and less glycogen than normal. The rate of cell division, as indicated by autoradiography, is higher on both sides of the liver than after splanchnic division alone and is particularly increased in the hormone influenced lobes, panel on left. Upper panels, hematoxylin and eosin, ×120; middle panels, electron micrography; ×1,700; and lower panels, autoradiography, ×300.

Fig. 10

Relative thymidine uptake of the right, R, and left, L, liver lobes after partial portacaval transposition. The method of calculation, the nomenclature and the statistical comparisons are the same as in Figure 6. The right liver lobes, which in this preparation received the total splanchnic venous return, had significantly greater deoxyribonucleic acid synthesis, groups 10, 11 and 12, except when pancreatectomy was superimposed upon delayed 30 per cent hepatic resection, group 13.