HEMATOLOGIC CHANGES
In most patients the hemoglobin and hematocrit are in the normal or low range.232 Blood volume is increased, and the red cell mass is actually increased in some patients. In severe thyrotoxicosis, normocytic anemia with hemoglobin concentrations as low as 8 - 9 g/dl may be observed. Hyperthyroid patients with anemia may show impaired iron use.232,233 Malnutrition may play a role in this decrease. These anemias are unresponsive to hematinic therapy, but the blood picture returns to normal when the thyrotoxicosisis controlled.234 Iron deficiency or megaloblastic anemia is exceptional and requires a search for some explanation other than thyrotoxicosis. It is possible that thyrotoxicosis may increase the need for vitamin B12, as shown experimentally, and perhaps for folic acid. Also, there is an increased incidence of antigastric antibodies and mild pernicious anemia in patients with Graves' disease.The glucose-6-phosphate dehydrogenase activity of red cells is increased in thyrotoxicosis.235
A relative lymphocytosis is frequently found in the peripheral blood due to neutropenia.236 A relative and an absolute increase in the number of monocytes was noted years ago.237 The monocyte count was between 10 and 15%; in only 2 of the 30 cases was it less than 10%. Relative lymphocytosis and relative monocytosis, with a normal or slightly low total white cell count, constitute the characteristic blood findings of Graves' disease. There is also an increase in the percentage and number of B lymphocytes and, as discussed previously, an altered ratio of T lymphocyte subsets. Significant pancytopenia with leukocyte counts under 3x10-9/l and neutrophiles under 2x10-9/l occasionally occurs, and if unrelated to drug therapy, tends to recover during treatment (237.1).
Graves' disease is often associated with mild thrombocytopenia, and occasionally with idiopathic thrombocytopenic purpura.238 This co-occurrence is thought to reflect the autoimmune pathogenesis of both diseases. Fourteen percent of patients with ITP are reported to have coincident Graves' disease. Mild thrombocytopenia may disappear spontaneously or with treatment of hyperthyroidism, or if severe, may respond to glucocorticoid therapy.239 Other more severe cases are managed as typical cases of ITP. Bone marrow examination may show normal or increased megakaryocytes.239 Hyperthyroidism also induces a shortened platelet life span, believed to be due to more rapid clearing of normal platelets by an activated reticulo-endothelial system. Both anti-platelet antibodies and shortened platelet life span could contribute to the low or low-normal levels of platelets found in Graves' patients. It is reported that all patients with Graves' disease have evidence of IgG bound to platelets.
Coagulation is usually normal in spite of mild prolongation of the prothrombin time. Antihemophilic factor is often elevated in level and returns to normal with treatment.240 Hyperthyroidism can be associated with increased coagulability, in part through elevation of factor VIII. Cerebral venous thrombosis has been reported in association with thyrotoxicosis, suggesting that occasionally the propensity for coagulation can lead to serious consequences (240.1). Capillary fragility is increased. Severe liver damage caused by thyrotoxicosis and secondary congestive heart failure may be associated with a hemorrhagic tendency.
The reticuloendothelial and lymphocytic systems undergo hyperplasia. There may be generalized lymphadenopathy, and the thymus may be enlarged. Occasionally the thymus presents as an anterior mediastinal mass, but diminishes to normal size with control of the thyrotoxicosis.241 Some authors have reported that the spleen tip can be felt in 20% of patients, but in our experience this finding is not common. The autoimmune responses in these patients have been detailed above. Several markers of augmented immune activity are elevated, including soluble CD30, a molecule released by T helper 2 cells, and IL-6 241.1.
The appetite is characteristically increased. The effect of this increase is to offset, in part (sometimes completely), the loss of weight that might be expected from the increased catabolism. Indeed, the pattern of weight loss with increased appetite is nearly pathognomonic of thyrotoxicosis, although it may occur in diabetes mellitus and malabsorption or intestinal parasitism. A minority of patients complain of anorexia. Needless to say, they are likely to show the greatest weight loss. Nausea and vomiting are rare, but when they occur, they are serious. They are usually features of severe thyrotoxicosis but may also reflect hypercalcemia. In the presence of hypermetabolism, vomiting leads quickly to dehydration, ketosis, and perhaps avitaminosis.
The incidence of achlorhydria in exophthalmic goiter was found some years ago to be approximately 40% and slightly higher in myxedema. 242 The figures would be lower today. Berryhill and Williams 243 found that 73% showed a return of free hydrochloric acid after surgical thyroidectomy. Gastric enzyme production is decreased, and a mild chronic gastritis may be present.244 Fasting serum gastrin levels, and responses to arginine, are increased.245
Abdominal pain is an occasional symptom of thyrotoxicosis. Its nature and origin are obscure. Epigastric pain may suggest ulcer, gallbladder disease, or pancreatitis. Vomiting is sometimes associated with the pain.
The rate of absorption from the gastrointestinal tract is accelerated. The glucose tolerance curve may show an abnormally rapid rise and fall. Absorption of vitamin A is enhanced, and vitamin A formation from carotene is also increased.
Increased frequency of normal bowel movements is common, and occasionally diarrhea occurs. Transit time is decreased, and fat absorption may be impaired to the point of steatorrhea if fat intake is excessive.246
The liver is frequently palpable in the absence of congestive heart failure, and is typically palpable with heart failure. Evidence of mild to severe liver disease may be found.247 The plasma albumin level may be below 4 g/dl, and the globulin level above 3 g/dl. Galactose tolerance is impaired. There may be mild elevation of PT. The LFTs can give the impression of viral hepatitis. For example in one survey of 81 thyrotoxic patients, three-fourths had some LFT abnormality, including 31% with elevated bilirubin, 24% with elevated SGOT, 13% with elevated LDH, 26% with elevated SGPT, and 67% with elevated alkaline phosphatase (which of course may reflect bone metabolism). Cholesterol is often depressed. The abnormalities clear with treatment.248 Bilirubin retention and jaundice are occasionally seen without evidence of congestive heart failure, but they are much more commonly found when this complication is also present. On hepatic biopsy the liver may be entirely normal histologically, even when there are abnormalities in chemical findings; alternatively, there may be evidence of focal collections of lymphocytes, decrease in glycogen, and occasionally death of cells. On electron microscopy, the mitochondria are increased in size and the smooth endoplasmic reticulum is hypertrophic. The glycogen level is decreased.249 The fine stellate scarrings seen in the livers of patients with severe thyrotoxicosis and reported in the earlier literature are rarely observed today. The cause of hepatic disease has been thought to be congestive heart failure, malnutrition, intercurrent infections, and a direct toxic effect of thyroid hormone. Malnutrition must play a role. Congestive heart failure by itself certainly can induce gross abnormalities in liver function, and presumably this insult is worsened by coincident thyrotoxicosis. The splanchnic blood flow is increased in thyrotoxicosis and the arteriovenous oxygen difference is greater than normal, but hepatic anoxia, at least in the portal areas, might occur even without circulatory failure if the metabolic demand for oxygen exceeds the supply.
Several patients who have been jaundiced without signs of congestive heart failure or other cause of hepatic dysfunction have been reported.250 In two of these patients there was considerable elevation of the indirect-reacting bilirubin level. Studies in one patient showed that conjugation products of glucuronic acid were secreted into the urine in greatly increased quantities. This finding ruled out any absolute deficiency in the glucuronyl transferase enzyme in the liver. It was hypothesized that in certain thyrotoxic patients there is a great increase in metabolites that must be excreted via the glucuronyl transferase enzyme system. Since bilirubin competes relatively inefficiently in this enzyme system, it may be "crowded out" in the presence of an increased quantity of substrates. As a result, it may not be conjugated as rapidly as normally, and its concentration in the serum would therefore rise. All of these patients had residual abnormalities in bilirubin metabolism when euthyroid. This finding suggests that an underlying abnormality was present and was exacerbated by thyrotoxicosis. It is probable that the occasional thyrotoxic and jaundiced patient may actually suffer from an unrecognized separate abnormality, such as Gilbert's disease or posthepatitic liver dysfunction, brought to light by thyrotoxicosis.
Polyuria and occasionally glycosuria are seen in uncomplicated thyrotoxicosis. Standard clinical renal function tests give normal results. Glycosuria may reflect accelerated absorption of sugar from the intestine and glucose intolerance.
In hyperthyroid animals and humans, the glomerular filtration rate and renal blood flow are on average increased, as are tubular transfer maxima for glucose and diodrast. The glomerular filtration rate and renal blood flow alterations probably are secondary to increased cardiac output, whereas the increased tubular activity may be a direct effect of thyroid hormone on renal function.251 Polyuria does not indicate insensitivity to vasopressin, for the kidney responds normally to vasopressin with an increase in concentration of urine.252
Hypercalcemia is a feature of severe thyrotoxicosis, but it rarely injures the kidneys. Occasionally hyposthenuria and uremia occur, 191,192 or more selective renal damage takes place. Huth et al.253 reported a patient with renal tubular acidosis coincident with hyperthyroidism. Circumstantial evidence suggested that hyperthyroidism led to hypercalcemia, which in turn had damaged the renal medulla and produced acidosis.
