Published in: Annals of Internal Medicine, volume 53, no. 4, pp. 647-655 (October, 1960):

John H. Frenster, M.D.
The Rockefeller Institute, New York, N.Y. 10021

Introduction:
History:
Documented Examples:
1. Hemoglobin Synthesis:
2. Blood Propulsion:
3. Albumin synthesis:
4. Osteoid Calcification:
5. Pulmonary Vascular Flow:
6. Ammonium Production:
7. Iodide Organification:
8. Aldosterone Inactivation:
9. Insulin Synthesis:
Suggestive Examples:
Discussion:
Summary:
Support:
Bibliography:
Additional References:
Links:

High-output failure in man has been described both for cardiac blood-propulsion (1) and for bone marrow erythropoiesis (2), but it also occurs in a wide variety of processes in other organs. It seems implicit in all descriptions of "relative failure" or "relative insufficiency" of the function of an organ (2). The usual response of an organ process when it remains subjected to increased loads is a secondary increase in the capacity to perform the affected function. Such functional hypertrophy has limits, beyond which the increased capacity becomes inadequate for the increasing load. At this point, failure of the function becomes evident despite output levels greater than normal. There appear to be both normal and pathologic limits to an increase in capacity for a given function. This article will review from the literature various examples of high-output failure in man, and will illustrate the occurrence of pathologic limits to the increase of capacity in certain of these examples.

History:

Meltzer in 1906 first discussed the reserve capacity of many different body processes in man, with emphasis on the ability of organs to reach performance levels above those occuuring normally (3). With the subsequent intensive development of quantitative techniques in human physiology, increased activity of organ processes could be detected in diverse states. By 1925, Liljestrand and Stenstrom could demonstrate high-output cardiac failure in patients with thyrotoxicosis or severe anemia (4). In 1940 Dameshek and Schwartz could summarize evidence for high-output marrow erythropoietic failure in patients with acute hemolytic anemia (5). Huckabee, Caston and Harrison, in 1950 classified cardiac failure types by physiologic categories, including an increased-load, high-output failure state (6). In 1952 Crosby and Akeroyd first determined the normal and pathologic limits to maximal hypertrophy of marrow erythropoiesis (7), and Singer in 1955 termed the submaximal pathologic state "dyserythropoiesis" (8). By 1957 Moore was able to describe examples of selective high-output failure of each of the three basic bone marrow functions (2), and recently the hypo-albuminemia of patients with the nephrotic syndrome has been ascribed to high-output failure of hepatic albumin synthesis (9).

Documented Examples:

The following body processes have been well shown to display high-output failure in certain disease states, with each of these also demonstrating pathologic limits to maximal hypertrophy of capacity (table 1).

1. Hemoglobin synthesis:

In normal subjects the rate of hemoglobin synthesis is 6.25 gm./70 kg./day (7, 10). In patients with congenital spherocytosis this rate is often maximally increased to 600 to 800% of normal (7, 10, 11) but, by contrast, in patients with sickle cell anemia this rate is not increased to more than 200 to 400% or normal, despite continued anemia (7, 10, 11). This appears to indicate a pathologic limit to full hypertrophy of bone marrow capacity to synthesize hemoglobin in patients with sickle cell anemia, and it may be related to the extensive fibrotic lesions in the bone marrow of these patients (12).

Despite these increased rates, high-output failure of bone marrow hemoglobin synthesis in both of these diseases is evidenced by the anemia (whole blood hemoglobin < 12 gm. %) that these patients display. Pathologic limits to full hypertrophy of bone marrow capacity to synthesize hemoglobin are similarly present in patients with the high-output failure states of pernicious anemia (11, 13), acquired immunohemolytic anemia (10, 11), thalassemia major (11, 14), hepatic cirrhosis (11, 15), chronic lymphatic leukemia (16), myeloid metaplsaia (11), and disseminated carcinoma (17).

2. Blood Propulsion:

In normal resting subjects the rate of cadiac output is 3.0 to 3.5 L./min./M² (18, 19). In patients with thyrotoxicosis this rate is often maximally increased during rest to 300% of normal (19), but, by contrast, in patients with athiaminosis this rate is not increased during rest to more than 200% of normal (20), despite continued congestive failure. This appears to indicate a patholgic limit to full hypertrophy of cardiac capacity to propel blood in patients with athiaminosis, and it may be related to the deleterious effects of athiaminosis on oxidative phosphorylation in cardiac muscle (21).

Despite these increased rates, high-output failure of cardiac propulsion of blood in both of these diseases is apparent in the hemodynamic evidence of congestive failure (ventricular end-diastolic pressure > 10 mm. Hg) that these patients display (19, 20). Pathologic limits to full hypertrophy of cardiac output are similarly present in patients with the high-output failure states of severe chronic anemia (22) and chronic cor pulmonale (23).

3. Albumin Synthesis:

In normal subjects the rate of albumin synthesis is 13.0 gm./70 Kg./day (24). In normal plasma donors in whom the erythrocytes are re-infused after separation from the plasma this rate is often maximally increased to 400% of normal (25), but, by contrast, in patients with the nephrotic syndrome in relapse this rate is not increased to more than 200% of normal (26), despite continued hypoalbuminemia. This appears to indicate a pathologic limit to full hypertrophy of hepatic capacity to synthesize albumin in patients with the nephrotic syndrome in relapse, and it may be related to hepatic hypometabolism secondary to the excessive urinary loss of thyroid hormone seen in these patients (27).

Despite these increased rates, high-output failure of hepatic albumin synthesis in both of these states is evidenced by the hypoalbuminemia (plasma albumin < 2.5 gm.%) that these patients display.

4. Osteoid Calcification:

In normal subjects the rate of osseous calcification of bone osteoid is 0.08 to 0.17 distal calcium pools/70 Kg./day (28). In patients with extensive Paget's Disease (osteitis deformans), this rate is often maximally increased to 500% of normal (28), but, by contrast, in patients with severe thyrotoxic osteoporosis this rate is not increased to more than 150% of normal (28), despite continued microscopic evidence of uncalcified osteoid. This appears to indicate a pathologic limit to full hypertrophy of the osseous capacity to calcify bone osteoid in patients with severe thyrotoxic osteoporosis, and it may be related to increased osseous blood flow in these patients (28).

Despite these increased rates, high-output failure of osseous calcification of bone osteoid is evidenced in both diseases by the uncalcified bone osteoid seen microscopically in these patients (29).

5. Pulmonary Vascular Flow:

In normal resting subjects the rate of pulmonary vascular flow is 3.0 to 3.5 L./min./M² (18). In children with atrial septal defect this rate is often maximally increased during rest to 400 to 600% of normal (30), but, by contrast, in adults with atrial septal defect this rate is not increased during rest to more than 300% of normal, despite continued pulmonary hypertension (30). This appears to indicate a pathologic limit to full hypertrophy of the pulmonary vascular capacity to conduct blood in adult patients with atrial septal defect, and it may be related to the proliferative pulmonary endarteritis seen in these adult patients (31).

Despite these increased rates, high-output failure of pulmonary vascular conduction of blood in both of these states is evidenced by the pulmonary hypertension (pulmonary artery systolic pressure > 30 mm. Hg) that these patients display (30).

6. Ammonium Production:

In normal subjects the rate of renal ammonium production is 30 to 50 mEq./Kg./day (32). In patients with diabetic acidosis but without azotemia this rate is often maximally increased to 500% of normal (33), but, by contrast, in patients with diabetic acidosis in whom azotemia has supervened this rate is not increased to more than 300% of normal (34), despite continued evidence of plasma acidosis. This appears to indicate a pathologic limit to full hypertrophy of the renal capacity to produce ammonium ion in patients with diabetic acidosis in whom azotemia has supervened, and it may be related to the deleterious effect of decreased renal blood flow on tubular function in these patients (35).

Despite these increased rates, high-output failure of renal production of ammonium ion in both of these states is evidenced by the plasma acidosis (plasma pH < 7.35) that these patients display (36).

7. Iodide Organification:

In normal subjects the rate of thyroidal iodide organification is 50 to 150 ug./70Kg./day (37). In patients with congenital goitrous cretinism this rate is often maximally increased to 1,000% of normal (38), but, by contrast, in patients with the nephrotic syndrome in relapse this rate is not increased to more than 150% of normal (39), despite continued hypometabolism and subnormal plasma organic iodine levels. This appears to indicate a pathologic limit to full hypertrophy of the thyroidal capacity to organify iodide in patients with the nephrotic syndrome in relapse, and it may be related to the deleterious effect of general body protein depletion on pituitary production of thyrotrpin in these patients (39).

Despite these increased rates, high-output failure of thyroidal organification of iodide is evidenced in both diseases by the hypometabolism and deficiency of thyroid hormone (serum protein-bound iodine < 3.0 ug.%) that these patients display (38, 39).

8. Aldosterone Inactivation:

In normal subjects the rate of hepatic inactivation and conjugation of aldosterone is 3.0 ug./70 Kg./day (40). In patients during normal pregnancy this rate is often maximally increased to 700% of normal (41), but, by contrast, in patients during toxemic pregnancy this rate is not increased to more than 400% of normal (41), despite the continued presence of increased quantities of active "free" aldosterone. This appears to indicate a pathologic limit to full hypertrophy of the hepatic capacity to inactivate and conjugate aldersterone in patients during toxemic pregnancy, and it may be related to the thrombonecrotic lesions in the livers of these patients (42).

Despite these increased rates, high-output failure of hepatic inactivation and conjugation of aldosterone is evidenced in both states by the elevated levels of "free" aldosterone in the urine (urine "free" aldosterone > 1.0 ug./70 Kg./day) that these patients display (41).

9. Insulin Synthesis:

In normal subjects the rate of pancreatic islet synthesis of insulin is 48 units/70 Kg./day (43). In the fetuses of prediabetic mothers this rate is often maximally increased to 3,600% of normal (44), but, by contrast, in adult patients with "growth" acromegaly this rate is not increased to more than 2,000% of normal (45), despite continued evidence of insulin deficiency and intolerance for glucose. This appears to indicate a pathologic limit to full hypertrophy of the pancreatic islet capacity to synthesize insulin in patients with "growth" acromegaly, and it may be related to the proliferative islet lesions produced by growth hormone (46).

Despite these increased rates, high-output failure of pancreatic islet synthesis of insulin is evidenced in both states by the insulin insufficiency (increased weight and stillbirth rate in fetuses (47), glucose intolerance in adults (48)) that these patients display.

Suggestive Examples:

Additional suggestive examples in man of high-output failure and of the normal and pathologic limits to increased capacity are outlined in table 2.

Physiologic techniques for quantitating function in these organ processes in man have not yet been applied or are still too imprecise to permit definitive documentation.

Discussion:

It seems apparent that an organ can fail in performing a given function in either an "absolute" or a "relative" manner. "Absolute failure" of a body process implies inadequate output when the process is presented with normal loads of work to be accomplished. "Relative failure" implies supernormal but nevertheless inadequate output when the process is presented with greater-than-normal loads.

Of fundamental interest is the ability of an organ to increase its capacity when subjected to prolonged increases of imposed loads. Acutely increased loads to an organ usually lead to a state of temporary disequilibrium, which tends to be moderated by the body mechanisms for homeostasis (67), resulting either in the rapid, increased utilization of previously unused reserve capacity in the organ, or in the slow, new formation of increased capacity. Homeostatic mechanisms which increase capacity can operate entirely within the affected organ, as in the sensitivity of the liver cells to hypoalbuminemia (68), or in the responsiveness of cardiac muscle to increased stretching (69); or they can operate by increased activity of a second organ, as in the increased production of erythropoietin by the anemic kidney (70), or in the increased production of corticotropin by the hypocorticoid pituitary (71, 72).

Functional hypertrophy in a given process can thus be pathologically limited either by an inadequate stimulation from the homeostatic mechanism or, as seems more frequent, by the inability of the failing organ to respond to such homeostatic stimulation. Such inability often seems to be a direct consequence of the disease process, as in the bone marrow fibrosis in patients with sickle cell anemia (12), in the pulmonary endarteritis in adults with atrial septal defect (31), or in the thrombonecrotic hepatic lesions in patients with toxemic pregnancy (42).

Such limiting lesions may be much more difficult to treat than are the abnormally large loads imposed on the failing organ. Reduction of such loads is the essence of successful therapy in disease states of high-output failure.

Summary:

The widespread occurrence of high-output failure in man has been reviewed for both well documented and suggestive examples.

The occurrence of pathologic limits to functional hypertrophy in each of these processes has been illustrated.

The failure of homeostasis implicit in such pathologic limits has been discussed.

Support:

Assisted by a Post-Doctoral Fellowship Grant from the American Cancer Society.

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1. Frenster JH, "Interaction of Load, Capacity and Resistance in Body Processes", Perspectives in Biology and Medicine 4: 152-158 (Winter, 1961).

2. Frenster JH, "The Magnitude of Disease as Measured by Tolerance Tests", J. Theoret. Biol. 2: 159-164 (1962).

3. Frenster JH, "Load Tolerance as a Quantitative Estimate of Health", Annals Int. Med. 57: 788-794 (Nov. 1962).

4. Editorial: "Medical Feudalism", J. Am. Med. Assoc. 184: 1039 (June 29, 1963).

5. Frenster JH, "Human Throughput Systems", Proc. 16th Ann. Conf. Engin. Med. Biol. 16: 164-165 (Nov. 18, 1963).

6. Frenster JH, "Analysis of Queueing and Renewal within Human Systems", Nature 207: 1139-1140 (Sept. 11, 1965).

7. Frenster JH, "Medicine 275: Systems Analysis of Latent Disease", Stanford University School of Medicine Catalog, 1972.