The etiology of both appears complex and the likely nature of some of the factors involved is indicated. The icterogenic triterpenic acids have proven to be valuable tools in the study of interferences in bile secretion in yellow fatheads. The symptomatology observed in the various stages of yellow fathead syndrome has been described in an earlier article (Brown, 1966a).
There were a few prodromal cases discovered by the author that allowed symptoms to develop to the required stage of the disease. The basic symptoms of different degrees of geeldikkop are the same in all cases of the disease (Brown, 1966a). In the final stages of this work, the daily progression of the disease was followed in various cases until recovery or death occurred.
The preparation of the reagents used in the determination of copper is described in Appendix 9. About a quarter of the sheep showed old calcified lesions of oesophagostomiasis in the intestinal tract.
CHAPTER 3
Plasma bile pigment concentrations in typical early disease cases are presented in Table 8. Data on plasma bile pigments from advanced and cured disease cases are presented in Table 9. Most of the pigment in the plasma of these animals consists of bilirubin, rather than its glucuronides.
Values for bilirubin glucuronides in the plasma of the sheep in question are included in the latter table for comparison. Thus, mild increases in free protoporphyrin were observed in erythrocytes in 20.8 percent of the cases studied. The elevations encountered in the mentioned cases of yellow fathead may be an expression of the existing hemolytic condition.
Only 37 percent of the control animals had detectable amounts of coproporphyrin present in the feces. Accuracy aside, the fact remains that low levels of porphyrin are detectable in the blood of these animals. The copper content in the liver was higher in seven out of nine cases of the yellow fathead than that in the control animals.
The reader is reminded of the marked increases in ceruloplasmin (a copper containing oc 2-globulin) found in the plasma of these animals.
CHAPTER 5
Evidence that the major conjugates of bilirubin excreted in the bile of sheep are glucuronides is presented in one of the later chapters. Thereafter, tolerance to the loading dose of glucose increases until normal curves are obtained in many of the advanced cases and in the recovered cases. This is the case because of the presence of an insulin-independent fructokinase in the liver and, to a lesser extent, in muscle and brain (Forsham & Mortimore, 1959).
Under the laboratory conditions at the time, virtually no lactic acid could be determined in the blood of the control sheep. The levels of oc-ketoglutarate were, if anything, slightly higher in the early cases of the disease than in the other groups of animals. The activity levels of succinic dehydrogenase and isocitric dehydrogenase in the livers of cases of different stages of geldikkop and the control animals were determined.
The mean value for succinic dehydrogenase found in Karoo sheep livers is 190. Activity levels found in advanced cases (mean value = 205) were generally higher than in early cases, but were in the same general order as control animals. Levels of glutathione reductase in the livers of control animals and cases of different stages of geeldikkop are shown in Table 51.
Extremely high levels of the enzyme were still found in the advanced cases, while the recovered cases produced values similar to those found in Onderstepoort sheep. Glutathione reductase occurs mainly in the cytoplasmic juice, where most but not all of the glycolytic enzymes of the cell are located (Gallagher, 1964). High values were found to persist in many of the advanced cases and in the recovered animals.
In the more typical type of cases, there is a hyperglycemic tendency instead of the low blood sugars seen in the very severe cases. The most important site of action of insulin is localized as before glucose-6-phosphate in the metabolic events of glucose (Kaneko, 1963). The opposing reaction is catalyzed by the enzyme glucose-6-phosphatase, which is found mainly in the liver.
CHAPTER 6
The erythrocyte methemoglobin reductase systems of animals originating mainly from the Karoo appear to be considerably less efficient than those of Transvaal-bred animals. The test is an in vitro method that actually indirectly measures glucose-6-phosphate dehydrogenase (G-6-PD) activity in the case of human red blood cells. In the case of the sheep erythrocyte, it is likely that this is actually an indirect measurement of glyceraldehyde phosphate dehydrogenase (GAPD) (see section 4 below).
The ability of sheep red cells to reduce MetHb varies considerably from sheep to sheep. Test results in cases representing all stages of geldikkop and in control animals are shown in Table 55. During subsequent field investigations, many of the early geldikkop cases were found to give different values.
Levels of the enzyme were studied in cases of all stages of geeldikkop and in controls. In view of the marked reductions in the activity levels of glyceraldehyde phosphate dehydrogenase in the erythrocytes in many cases of all stages of jaundice, the levels of glutathione and DPN present in these cells become of immediate importance. Glutathione and total pyridine nucleotide levels in the erythrocytes in the different stages of jaundice and control animals.
The two high values found in the recovered Sheep V3-4 and Y3-3 are associated with low values of the dehydrogenase. The values for red cell total pyridine nucleotides found in the jaundice cases are generally lower than those found for the red cells of the control group. This, in turn, must have a profound effect on the permeability and integrity of the red cell membrane.
Comparisons were made of the levels of some enzymes involved in glycolysis in erythrocytes of different species. In Chapter 5, it was stated that disturbances in membrane transmission can be widespread in the body tissues of affected animals, which includes e.g. At all stages of the disease, urea, creatinine, uric acid and total amino acids were determined in the blood.
3-5 'days
CHAPTER 8
We draw the reader's attention to the following important points arising from the discussion so far: a) severe hematological disorders observed in prodromal cases, e.g. leukopenia, thrombocytopenia and anemia, and the severe hypoglycemia that occurs in these cases; Potassium values were generally quite normal, but most of the chloride values found were still low. Dehydration was also prominent in many advanced cases showing features of geeldikkop and enzootic icterus, e.g.
Extremely severe atrophy of the gastrointestinal tract was a constant feature in all these cases (Brown et a!., 1960). Microscopic examination showed evidence of atrophy of the lymphoid tissue, along with a decrease in the cellular content of the Malpighian bodies of the spleen and the cortical nodes of the lymph nodes. Adrenals of typical early cases (Sheep Vl-) showed marked degenerative changes at autopsy.
The same changes as in early cases were found in advanced cases of the disease, with prefix V 1- and cases showing features of geeldikkop and enzootic icterus. Adrenals of early and advanced cases generally appeared on microscopic examination enlarged with a rather indistinct texture. Atrophy of lymphoid tissue was a common finding in both early and advanced cases; many of the lymph nodes examined contained numerous macrophages loaded with iron-containing pigment.
In the pathology of the recovered cases, nothing special about the kidneys and lymphoid tissues was evident. This phenomenon, showing an increased rate of destruction of erythrocytes, is further evidence of the existence of a hemolytic process in the general course of cases of geldikkop. The results of the macroscopic examination of the kidneys of geeldikkop cases indicate the obvious involvement of these structures in the pathogenesis of the syndrome.
Evidence has been given of severe disorders existing in carbohydrate metabolism in these cases. Arsphenamine jaundice is associated with lesions in the portal triad, swelling of the bile ducts and cholangioli. More water than bile may flow backwards resulting in inspiration of biliary solids (Popper & Schaffner, 1957).
