Discussion of Questions
1. true
2. true
3. (c) decreased hepatic production, and (d) increased vascular permeability
Discussants:
Dr. R. Zimlichman. Head of the Department of Internal Medicine F, and Chief of the
Hypertension Unit, Edith Wolfson
Hospital , Holon, Israel
Dr. H. Eliahou. Research Associate of the Hypertension Clinic, Edith Wolfson Hospital,
Tel-Aviv University School
of Medicine, Tel-Aviv, Israel.
Dr. R. Zimlichman:
This patient presented with an unusual and rather rare clinical picture. In this subgroup of
patients we see a very mild form of diabetes mellitus, minimal hyperglycemia, or euglycemia, yet
they have a clearly abnormal glucose tolerance test (GTT). The clinical expression of end organ
damage is disproportionate to the severity of the diabetes . Despite almost normal glucose levels,
these patients develop moderate to severe chronic renal failure, retinopathy and evidence of
vascular damage presenting with proteinuria, vision loss, and/or peripheral vascular disease. They
present signs of a chronic disease, like weight loss which is sometimes camouflaged by the fluid
retention, general weakness, loss of appetite, loss of libido, sometimes secondary depression, and
often anemia of the microcytic normochromic type.
This group of patients, like the one presented, usually suffer from hypoalbuminemia disproportionate
to the urine protein loss. My assumption is that as a part of the chronic disease manifestations,
decreased hepatic albumin production is present despite the absence of overt hepatic
dysfunction.
The prognosis of this group of patients is usually bad. Many of them suffer from iatrogenic
complications which are mainly induced by contrast media injected during the process of angiography
for the evaluation of PVD or in the intra-venous pyelographies. The danger of these procedures is
prominent especially when preventive measures such as adequate hydration, are not practised.
Why do such diabetic patients, who are almost euglycemic, have such a grave prognosis? Today
we are
able to understand these phenomena much better than a few decades ago. Patients in this group
usually have multiple vascular risk factors. In our patient, hypertension, and hyperlipidemia with
association of heavy smoking in the past, and positive family history of CVD, were present. All
these factors can explain the accelerated atherosclerosis, even when blood glucose levels were only
mildly elevated. My assumption is that this patient, like most other patients in this group, is
hyperinsulinemic. Hyperinsulinemia, with the resulting accelerated atherosclerosis, is the price
that
this patient has to pay for maintaining euglycemia. I believe that this patient represents a
specific subgroup of diabetic patients with relative euglycemia but with a grave prognosis. Usually
these patients are identified easily on clinical grounds. Further studies are needed to identify
these specific patients and to try to determine the pathogenesis of their accelerated
atherosclerosis and their early and rapid target organ damage.
Dr. H. Eliahou:
This is a case of severe NIDDM with very high glycosylation of hemoglobin, despite the fact that he
is not obese and despite the fact that his blood sugar is not very high. The HbA1c, which is a
good objective measure of glucose control (1,2) reached a value of 13.9% a month or so before his
first admission. It was reduced after treatment to 11.2% and on admission to 9% after therapy and
blood glucose control. This in itself is an indication that the patient's diabetes mellitus was
poorly controlled. He developed the full blown clinical picture of nephrotic syndrome. This was
associated with two rather uncommon clinical features:
1) A rather low value of urine protein excretion of about 4 g per day, which does not explain his
severe
nephrotic syndrome with severe hypoalbuminemia.
2) The hypoalbuminemia reverted to near normal after a very short while with standard therapy,
which included dietary supply of adequate number of calories and a sucrose-free diet. He had
received
plasma only twice, 2 units each time.
The question is where did his albumin go? The 3 possibilities are :
1) Lack of protein synthesis in the liver, due to the severity of the disease. There was neither
clinical (no signs of portal hypertension) nor laboratory evidence of hepatic dysfunction. (liver
function tests were normal).
2) Gastrointestinal loss of albumin. There were no gastro-intestinal symptoms or signs to support
this hypothesis. He has had no steatorrhea. His diet was that of low sugar only. He ate proteins
normally. He had no signs of vomiting or non-absorption.
3) Loss of albumin into the interstitial space due to the increased permeability of the vascular
walls secondary to the high glycosylation.
The last hypothesis is supported by the fact that he had a high level of glycosylation of
hemoglobin, and that with high protein diet the hypoalbuminemia was corrected rather quickly. The
glycosylation allows an increased permeability through the capillary walls, resulting in
retinopathy and nephropathy. It is presumed that the patient had developed severe glycosylation of
vascular wall proteins which resulted in a high permeability, allowing for loss of protein as well
as fluids into the interstitial spaces. It can be argued that this process is self limiting and that
another factor is responsible for the continued hypoalbuminemia. The rapidity with which this
hypoalbuminemia was corrected shows that even if other factors did play a role in its pathogenesis,
their role was rather minor and could be counteracted rather rapidly by simple means.
The transcapillary escape rate of albumin (TERalb) is an indicator of dysfunction of the
microvascular wall, i.e., a measure of the permeability of the vessels, indicating atherosclerotic
damage to these walls (3,4). The TERalb is the fraction of intravascular albumin which passes to the
extravascular space per unit time. This is expressed as the decrease in plasma radioactivity after
the injection of 123-I-albumin.
The TERalb is elevated in patients with diabetes mellitus especially in those who were poorly
controlled (5), even if the blood pressure is normal. Nevertheless, the escape rate is blood
pressure dependent, since the acute infusion of clonidine causes a decrease in TERalb parallel
to the decrease in systemic blood pressure (6). Nannipieri et al (7) found that TERalb was
increased
in the type 2 diabetic patient with albuminuria and that this loss was associated with the severity
of the HbA1c found in the blood, i.e., the higher the HbA1c, the greater the TERalb.
Bucala and Vlassara (8) in their in-depth review state that there is little doubt that the primary
cause of complications in diabetes is the hyperglycemia and that advanced glycosylation end products
act to increase vascular permeability. Furthermore, it was possible to reduce the clinical
manifestations of nephropathy and neuropathy by 30% to 60% when the intensively treated diabetics
were compared with conventionally treated patients (9).
In summary, we have a diabetic patient whose diabetes is of recent onset and of a seemingly
mild
nature, who developed serious end-organ damage associated with a very high HbA1c within a few
months, despite normoglycemia on many blood tests. This clinical entity seems to be a variant of
the common or the usually-seen diabetes mellitus, with hyperinsulinemia causing early
vasculopathy. The nephrotic syndrome which became severe in a very short time of only a few weeks,
seems to have been due to the markedly increased permeability of the vascular wall, since the
urinary losses of albumin were rather mild, ie <4 g/day and the HbA1c was high. Whether there
were
such associated phenomena as hepatic decrease in albumin production , as proposed by one of the
discussants (RZ) or a decrease in GI absorption of proteins, cannot be ruled out from the available
data. However, it does seem to me that the TERalb into the surrounding interstitial tissues could
play an important role in the development of the anasarca and the
hypoalbuminemia.
References
1. Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A. Correlation of glucose
regulation and hemoglobin A1c in diabetes mellitus. New Engl J Med 1976;295:417-420.
2. Larsen ML, Horder M, Mogensen EF. Effect of long-term monitoring of glycosylated hemoglobin
levels in insulin dependent diabetes mellitus. New Engl J Med 1990;323:1021-1025.
3. Tooke JE. Methodologies used in the study of microcirculation in diabetes mellitus.
Diabetes Metab Rev 1993;9:57-70.
4. Porta M, LaSelva M,Molinatti P, Molinatti GM. Endothelial cell function in diabetic
microangiopathy. Diabetologia 1987;30:601-609.
5. O'Hare JA, Ferris JB, Twomey B, O'Sullivan DJ. Poor metabolic control, hypertension, and
microangiopathy independentlyincrease the transcapillary escape rate of albumin in diabetes.
Diabetologia 1983;25:260-263.
6. Parving HH, Kastrup J, Smidt UM. Reduced transcapillary escape of albumin during acute blood
pressure lowering in type I (insulin dependent) diabetic patients with nephropathy.
Diabetologia 1985;28:797-801.
7. Nannipieri M, Rizzo L, Rapuano A, Pilo A, Penno G, Navalesi R. Increased transcapillary escape
rate of albumin in microalbuminuric type II diabetic patients. Diabetes Care 1995;18:1-9.
8. Bucala R , Vlassara H. Advanced glycosylation end products in diabetic renal and vascular
disease. Am J Kidney Dis 1995;26:875-888.
9. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment on
the development and progression of long-term complications in insulin-dependent diabetes mellitus.
New Engl J Med 1993;329:977-986.
I agree that the diagnosis of diabetic nephropathy is not clear in this patient. I also would like clear evidence of diabetic retinopathy. Also, it must be kept in mind that the degree of proteinuria and the extent of hypoalbuminemia may not alway
s correlate because of tubular catabolism of filtered albumin. Thus, it is possible to filter a great deal more albumin than actually appears in the urine.
David J. Leehey, M.D. (djleehey@aol.com)
Hines, IL U.S.A.-Monday, April 01, 1996 at 16:0
2:18 (CST)
Reply to Dr Pateras:
Thanks for your comment. You have put your finger on the very
point I wanted to make. I am trying to explain the discrepancy
between the intensity of the proteinuria and the intensity
of the hypoalbuminemia ( which you yourself have observed).
I believe that this lack of correlation occurs in the diabetic
and not in the nephritic, because of the glycosylation of the
proteins of the vascular walls and the insuing leakage of the
albumin into the extra-vascular spaces.
In answer to the specific questions:
1/ The patient claims that he was not diabetic 3-4 years ago.
2/ Biopsy of the kidney was not done.
3/ The diagnosis of membranous nephropathy is at least, clinically,
not likely. The patient was diabetic with hyperglycemia,
with elevated HbA1c, with retinopathy and even neuropathy.
4/ It is indeed likely that the hyperglycemia is responsible for the
complications,
Haskel Eliahou MD
Ramat Chen, Ramat-Gan Israel, 52241-Thursday, May 30, 1996 at 10:00:45 (CDT)