static neoplasia. Hypoglycaemia produced by tumours other than insulinomas is usually referred to as 'non-islet cell tumour hypoglycaemia' (NICTH) and has ...
Tumours Producing Hypoglycaemia Vincent Marks and J. D. Teale Department of Clinical Biochemist y and Nutrition, St Luke’s Hospital Guildford and School of Biological Sciences, University of Surrey, Guildford, Surrey GU2 5 X H , U .K .
I. INTRODUCTION For just a very brief period, between 1927 and 1930, tumours that produce hypoglycaemia were thought to arise exclusively within the pancreas and to secrete insulin. Since that time, however, it has become increasingly apparent that tumours developing almost anywhere in the body can cause hypoglycaemia, although the mechanism by which they do so is clearly not always the ~ a m e . l -Nevertheless, ~ there are some features common to most or all such tumours: (1) The hypoglycaemia is episodic and almost invariably of the fasting variety. (2) It is characteristically associated with hyporather than with hyper-ketonaemia? and only rarely is the patient desperately ill between hypoglycaemic episodes.
It is small wonder, therefore, that in the days before plasma hormone assays were commonplace there was often considerable confusion as to the nature and cause of a patient’s hypoglycaemia. The situation is still, however, far from absolutely clear.6 In this paper we will review what is currently known about the mechanisms by which various tumours produce spontaneous hypoglycaemia and how they can be distinguished pre-operatively. The tumours themselves can, broadly speaking, be divided into (a) adenomas and carcinomas of the pancreas; (b) mesenchymal tumours, especially fibro~arcomas~ and haemangiop e r i ~ y t o m a s ; ~(c) , ~ lymphomas;lO,ll (d) adrenal adenomas and carcinomas;l but also (e) carcinomas arising elsewhere in the body, especially the gastrointestinal tract and liver.l2,l3Hypoglycaemia arising from tumours other than insulinomas is often referred to as “non-islet cell tumour hypoglycaemia” (NICTH) and is of varied pathogenesis.
11. PANCREATIC ENDOCRINE TUMOURS Insulinomas, the name by which hypoglycaemia-producing endocrine tumours of the pancreas are generally known, are the commonest hormoneproducing tumours of the gastrointestinal tract,14 though sometimes they are excluded from consideration under this title.15 The best estimates are that insulin-secreting tumours occur with an incidence of about 1 case per million of the population per year.’&-18 More than 80% occur as solitary benign adenomas, composed mainly or exclusively of morphologically normal 8-cells. About 10% of insulin-secreting tumours are metastatic, i.e. malignant, whilst a further 10% are multiple but behave as benign. Women outnumber men in the ratio of 6:4 for benign but not for malignant insulinomas which, though recorded in children, are exceedingly rare below the age of 10.1
111. BENIGN INSULIN-SECRETING TUMOURS Clinically important insulinomas are generally between 10 and 20 mm in diameter, although occasionally tumours as large as 150 mm, or as small as 5 m m in diameter, have been incriminated in the production of symptomatic hypoglycaemia. Tumours of small size can easily be overlooked in resected pancreata or at postmortem unless the examination of the pancreas is extremely thorough. Tumours missed in this way may account for some of the negative pancreatic explorations in which partial pancreatectomy was followed by a complete remission. In such cases, and because no tumour was identified in the ablated specimen, the hypoglyca-
Diabetes/Metabolism Reviews, Vol. 7, No. 2, 79-91 (1991)
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emia may have been attributed to islet hyperplasia, which is a common histological finding in the pancreas of patients with proven insulinomas. The true incidence, therefore, of islet hyperplasia producing symptomatic hypoglycaemia is probably less than the number of published cases would suggest. The natural history of insulinomas suggests that, apart from their propensity for causing hypoglycaemia from which death may, though fortunately rarely does, result, they do not enlarge or become malignant with the passage of time. Cases in which there was documentary evidence for the presence of an insulin-secreting tumour extended over a period of 25 years or more have been p ~ b 1 i s h e d . lWith ~ modern diagnostic technology,2s26 the average time between onset of symptoms and diagnosis has fallen from several years in the middle part of this century to a little under a year nowadays.27The delay almost always results from a reluctance of the patient to seek help or the failure of the practitioner to suspect a hypoglycaemic aetiology rather than real difficulties in diagnosis.
IV. ECTOPIC INSULINOMAS Insulinomas are distributed evenly throughout the pancreas and only very rarely outside it. In this respect, as in the infrequency of their malignant transformation, insulinomas differ from all other types of hormone-producing tumours of the gastrointestinal tract. Less than 1% of the 677 insulinomas collected from the literature by Laurent et ~ 1prior . ~ to 1971 were located anywhere else than in the pancreas. A very few have been reported since then.28,29The commonest ectopic sites are the duodenum and the immediate vicinity of the pancreas itself.
V. HISTOLOGY A. Benign Insulinoma
Many insulinomas are composed entirely of seemingly normal B-cells, although more thorough examination, especially by electron microscopy and immunocytochemistry, usually reveals a small but variable number of other pancreatic endocrine cell types, of which somatostatin-containing Dcells are the commonest. Tumours show variable and unpredictable staining with immunohistological reagents,
including synaptophycin, neurone-specific enolase, and chromogranin, which have been used as general markers of neuroendocrine tumours or APUDomas. Attempts to classify insulinomas into clinically useful categories have been made since they were first identified some 60 or more years ago. It was recognized comparatively early that classical morphological and histological criteria used for distinguishing malignant from benign tumours were unreliable in the case of insulinsecreting neoplasms of the pancreas, and that only the presence of metastases, or their subsequent appearance, could be relied upon to make the distinction. More recently, Creutzfeld e t a/.’(’ have classified insulinomas into four types on the basis of their histological, ultramicroscopic, and immunocytological appearances. Type 1 is the commonest and accounts for almost half of the cases. In this type of tumour, virtually every cell contains typical P-granules. In the second commonest type (type 2), which accounted for 25% of the 28 cases in the series of cases studied by these authors,3u most of the cells contained, in addition to typical P-granules, a number of atypical granules which were demonstrably different from those of normal A, 8, D, or PP cells. These atypical granules bear a remarkable resemblance to coated P-granules which are found in small numbers in normal pcells and in which proinsulin is believed to be converted into insulin and C - ~ e p t i d eCreutzfeld .~~ et aL30 distinguished a third type of tumour in which the cells contained only atypical P-granules and no typical ones. Though not specifically identified as such, these may correspond to the proinsulinomas or proinsulin-secreting tumours that have been postulated to exist, but only very rarely identified pre-operatively and in life.” A fourth type recognized by the same investigators”’ and which included the only two malignant tumours in the series, showed none of the characteristic histological features of insulinomas. These tumours gave negative reactions with immunocytochemical and classical histological stains, but showed all of the ultramicroscopic signs of high functional activity. They would probably, in former times and in well-founded histopathological laboratories, have been classified as carcinoid tumours rather than ”insulinomas“. Berger et ~21.’~ classified hypoglycaemia-producing tumours of the pancreas from their functional rather than histological characteristics. Group A tumours were characterized functionally by the almost complete suppressibility of insulin
TUMOURS PRODUCING HYPOGLYCAEMIA
and proinsulin secretion, by either diazoxide or somatostatin, and histologically by an abundance of well-granulated @-cells in what the authors describe as a trabecular arrangement. Group B tumours were resistant to the suppressant effects of diazoxide and somatostatin and had fewer, less well-granulated P-granules with what the authors called a “medullary type” histological appearance. The two groups of patients had substantially different proportions of insulin to proinsulin and proinsulin-like components circulating in their blood pre-operatively. In the group B patients, roughly 46% of the total immunoreactive insulin was assessed as being due to proinsulin or proinsulin-like components, whereas in group A patients these constituents accounted for only 20% of the total immunoreactive insulin. This reflects the smaller proportion of coated to uncoated @-granulesin the cells of the group A than in the group B patients. Neither of the two new histological classifications enables the clinically important distinction between malignant and non-malignant tumours to be made. The recent observations-that malignant, but not benign, insulinomas express the achain of human chorionic gonadotrophin which can be detected immunocytochemically-held out hope of doing so, but no prospective studies have yet been published in which the method was employed and even the retrospective study results have not been confirmed.34 A substance with the histological appearance of amyloid has long been recognized as being present in insulinomas, both malignant and benign. It is identical to that present in increased amounts in the islets of many patients with noninsulin-dependent diabetes mellitus (NIDDM), and consists of a polypeptide of 37 amino acids which is co-deposited with a pentomeric amyloid protein (pentraxin) common to all varieties of amyloid. The islet amyloid polypeptide, also called amylin, was at one time thought to be involved in the aetiology of NIDDM. It is now known, however, to be co-produced and co-secreted with insulin by normal B-cells as well as those of insulinoma and NIDDM patient^.^^,^^ Why islet amyloid polypeptide should be deposited in much larger amounts in some insulinomas rather than others and whether it has any prognostic significance is still unknown.
B. Mixed Cell Tumours and Carcinoids Although a thorough search of resected benign insulinomas using immunocytochemical
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techniques almost invariably reveals the presence of isolated D and/or A-cells, their presence in greater numbers is usually associated with malignancy. Malignant islet cell tumours often have the classical histological appearances of a carcinoid tumour and may be associated with either no evidence of endocrinological disturbance during life, or an extremely varied one. Transformation in endocrinological behaviour from that of a glucagonoma to one of insulinoma and vice versa is not unknown, nor are the manifestations of ectopic hormone production characteristically seen with other types of malignant pancreatic tumour. Among the well-established linkages of insulinsecreting carcinomas of the pancreas with other endocrine syndromes are Cushing’s syndrome, Zollinger-Ellison syndrome, acromegaly, carcinoidosis, and hypersomat~statinaemia.~~ Malignant insulinomas and mixed cell tumours vary enormously in their aggressiven e ~ s Progress . ~ ~ from the first appearance of symptoms to death from inexorable hypoglycaemia is usually very rapid, unless chemotherapy is successful. Prolonged survival has, however, been reported in cases that have responded to anti-hypoglycaemic, tumoricidal, or ablative
the rap^.^^,^^ VI. AETIOLOGY OF PANCREATIC ENDOCRINE TUMOURS Insulinomas are, after parathyroid and pituitary adenomas, the commonest manifestation of MEN-1. They do not occur in other types of multiple endocrine adenomatosis. The familial occurrence of seemingly solitary insulinomas has also been reported, but whether this is a forrirr fruste of MEN-1 must await gene analysis. This has now become possible41 for MEN-1. Insulinomas occurring in children and young adults are particularly likely to have either MEN1 or the persistent functional hyperinsulinisrn of infancy, generally referred to as nesidioblastosis and which itself appears to have a strong genetic component.42 Indeed, in infants and young children below the age of 4, the histopathological features of solitary insulinomas resemble those of nesidioblastosis rather more than those of insulinomas in adults. Evidence that patients with insulinomas have extended family histories of diabetes mellitus is confined to a very few studies. It is, however, worthy of further consideration, since the incidence of benign insulinomas in patients with established type I1 diabetes is both well reco-
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gni~ed and ~ ~probably more common than in the general population. No incontrovertible evidence of insulinoma developing in a patient with established insulin-dependent diabetes mellitus (IDDM) has yet been published.
VII. OTHER TUMOURS Within 2 years of the first clinical description of hypoglycaemia caused by an insulin-secreting tumour, Doege had described a patient who had been operated upon for a large mediastinal tumour and who had had episodes of altered consciousness. The significance of these observations was not, however, appreciated until some 3 years later when the patient's symptoms recurred and proved to be hypoglycaemic in origin. Between 1930 and the present day, many hundreds of cases of hypoglycaemia caused by tumours originating outside the pancreas and composed of neither typical or atypical B-cells have been diagnosed. 1-3.7-9.44-53 The association that has attracted most interest over the years has been that between hypoglycaemia and large fibrosarcomas usually of low or moderate malignancy arising in the thorax or retroperitoneal space. Only a tiny minority of fibrosarcomas are associated with the develop* - ~ ~ hypoglycaemia men t of h y p o g l y ~ a e m i a . ~When does occur, it is usually not until very late in the course of the disease and the tumour itself is very large. Only very rarely do tumours under 500 g in weight cause hypoglycaemia; most weigh between 2 and 4 kg, but one weighing in excess of 20 kg has also been recorded.' Hypoglycaemia, once it has occurred, is generally profound and relentless, though often responsive to surgical ablation or even debulking of the tumour. In this respect, it is unlike benign insulinomas-where anything less than total removal is seldom effective-but like malignant tumours, where debulking, especially if the "primary" tumour has already been removed, is often effective in relieving the hypoglycaemia, sometimes for many years. Other tumour types of special interest because of their association with hypoglycaemia are adrenocortical adenomas and carcinomas, hepatomas, haemangiopericytomas, pheochromocytomas, lymphomas, and the l e u k a e m i a ~ . ~ ~ No type of tumour is exempt, however, and even tumours of the meninges have been responsible for producing hypoglycaemia.
It became apparent, very early on, that apart from their ability to produce non-fasting, nonketotic hypoglycaemia, these tumours had very little in common. The way in which they produce hypoglycaemia has, however, only comparatively recently begun to become apparent. It is not necessarily the same, even within single tumour types, but patterns are beginning to emerge. The exact incidence of tumour-induced hypoglycaemia is difficult to ascertain and no population study comparable with those for insulinoma has been published. In our own experience of cases referred from all over Britain, NICTH is about one quarter (25%) as common as insulinoma, but this is probably an underestimation as many cases go unrecognized.
VIII. PATHOGENESIS OF TUMOUR HYPOGLYCAEMIA A. Insulin-Producing Tumour Hypoglycaemia 1. Insulin
That insulin is the agent by which pancreatic endocrine tumours produce hypoglycaemia has not been seriously in doubt since their discovery. It was, however, believed for many years that there was an absolute overproduction of insulin by the tumour rather than, as is now quite apparent, inappropriate secretion during hypoglycaemia. It is this ability of insulin-secreting tumours of the pancreas to continue secreting insulin when normal healthy B-cells shut down insulin secretion completely that is both their hallmark and the way in which they produce fasting hypoglycaemia. Many insulinomas are unresponsive to the insulinotropic effects of intravenous glucose and fail to exhibit the characteristic early rise in plasma insulin seen following the rapid intravenous injection of glucose. Rather more tumours retain the capacity to respond to glucagon and the enteric hormones released into the bIood following ingestion of a meal and in some rare individuals this is responsible for their presentation with a history of reactive rather than fasting hypoglycaemia. The response of insulin-secreting tumours to other insulin secretagogues is likewise too unpredictable to be of either diagnostic or pathogenic significance.
TUMOURS PRODUCING HYPOGLYCAEMIA
The major way by which insulinomas produce fasting hypoglycaemia is by inhibiting hepatic glycogenolysis and gluconeogenesis, both of which ordinarily increase during fasting. Increased peripheral glucose uptake may occur but is seemingly not usually an important consideration in the aetiology of the hypoglycaemia. Nevertheless, circulating levels of insulin in peripheral blood are normally sufficiently high to prevent the rise in plasma free fatty acid and ketone bodies (P-hydroxybutyrate and acetoacetate) that accompanies prolonged fasting and most other types of spontaneous hypoglycaemia.
2. Proinsulin It has been known ever since the discovery of proinsulin that it ordinarily constitutes a much higher proportion of the circulating immunoreactive insulin in patients with insulinomas than in healthy people.57 This is especially so in patients with malignant tumours. It is still unclear why this should be so or whether the inability to process proinsulin properly is aetiologically important in the development of benign insulinsecreting tumours rather than being only a consequence of them.5s Very rarely, even benign tumours have been found to secrete proinsulin as their main and possibly sole insulin-like product, leading to the suggestion that they might be called "proinsulinoma~".~~
B. Non-insulin-Producing Tumour H ypoglycaemia Only with the emergence of improved immunological and molecular biological techniques has the mystery of the aetiology of hypoglycaemia by non-insulin-producing tumours-which has aroused so much interest over the years-begun to be The cause is clearly not the same in all cases but two mechanisms have already been identified with a high degree of certainty: unregulated overproduction of IGF-I1 by the tumour; and induction of autoantibody production to the insulin receptor by the subject's immune system. 10,11*63
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IX. THE INSULIN-LIKE GROWTH FACTORS: IGF-I AND IGF-I1 The identification of the insulin-like growth factors, their isolation, characterization, and nomenclature are beyond the scope of this review; it is sufficient to draw attention to the seminal work of Froesch and co-workers in Z ~ r i c h , ~ ~ + ~ , ~ ,van ~ Wyk and Daughaday et al. in St L O U ~ Sand co-workers in Chapel Hill.69 The insulin-like growth factors were first identified by their ability to mimic the effects of insulin on isolated tissues in uitro. They are responsible for most of the biological activity described in the earlier literature as due to nonsuppressible insulin-like activity (NISLA). Their greatest concentration is in serum from which they were first isolated and characterized.66 The non-suppressible insulin-like activity, which was used as the basis of their bioassay, was found to reside in two distinct chemical moieties, each bearing a marked secondary and tertiary structural resemblance to one another as well as to proinsulin, with which they share a number of biological effect^.^^,^^ The three molecules IGF-I, IGF-11, and proinsulin are, however, immunologically quite different from one another and immunoassays have been developed for each of them with little (in the case of the IGFs) or no cross-reactivity between them.70This clear separation of the three chemical species was not possible with any of the earlier bio- and radioreceptor assays, which undoubtedly accounts for much of the confusion that surrounds this topic in the earlier literature. Both IGF-I (which is identical to the somatomedin-C of the earlier literature) and IGF-I1 (but not proinsulin) circulate in the blood completely bound to a number of specific IGF binding proteins whose nomenclature is still far from u n i f ~ r m . ~ ~The , ~ ~binding ,~' proteins appear to have equal affinity for each of the two IGFs. The production of at least the major circulating binding protein (IGF-BP3) is linked, in some still poorly understood way, to the production of IGF-I, which is in turn linked to growth hormone action on the liver. Although IGF-I may be produced by many, if not all, tissue cell types, most of that present in the circulation is secreted into it by the liver. This is thought also to be the main, if not sole, source of the binding proteins. The source of the normal amounts of circulating IGF-I1 is less clear but there is no reason
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to believe that it is exclusively the liver. The concentration of both IGF-I and IGF-I1 in plasma is many hundreds of times more than that of insulin, whether expressed in molar or mass units. Nevertheless, it was appreciated long before they were isolated and characterized that neither exerts any insulin-like effect on either blood glucose or non-esterified fatty acid regulation in insulindependent diabetics-in whom circulating levels are normal-or healthy human subjects or animals in which all the manifestations of insulin deficiency can be produced by immune neutralization of insulin by insulin antibodies. Reports of increased circulating non-suppressible insulin-like activity (NSILA) in patients with tumour-induced hypoglycaemia began to appear in the literature at about the same time as evidence was accumulating that plasma levels of immunoreactive insulin were either normal or actually suppressed in patients with this condition. Reports also abounded of NSILA in tissue preparations made from these tumours but there was no unanimity as to whether it was due to ''soluble'' NSILAs or to an insoluble NSILP (non-suppressible insulin-like protein). With the benefit of hindsight, it now seems likely that NSILP72was an IGF-IGF-binding-protein complex rather than a novel compound. A. IGF-I1 A major breakthrough in our understanding of non-insulin-induced tumour hypoglycaemia came with the demonstration of greatly increased amounts of the mRNA of IGF-I1 in tumour tissue of patients with hypoglycaemia-producing t ~ m o u r sand ~ ~the more widespread availability of radioimmunoassays for circulating levels of IGF-I and IGF-II.71*73 Immunoassays for IGF-I preceded by many years the availability of assays for IGF-I1 and uniformly demonstrated low to very low levels in patients with hypoglycaemia from non-insulinsecreting tumours. This is in contrast to patients with insulinomas in whom IGF-I levels are normal or slightly elevated.74 Ron et aL50 described high levels of circulating IGF-I1 in two patients with tumour hypoglycaemia who also had attenuated or absent growth hormone responses to induced hypoglycaemia. This latter feature is common to most, if not all, patients with non-insulin tumourinduced hypoglycaemia in whom it is looked for regardless of the histology of the tumour. It had led us75 to speculate some years ago that these tumours might produce hypoglycaemia by
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inhibiting not only growth hormone secretion, but also the secretion of other peptide hormones including glucagon and insulin. Scepticism as to the aetiological significance of IGF-I1 in the genesis of tumour-induced hypoglycaemia grew as evidence accumulated that plasma IGF-I1 levels, though sometimes raised, were more often "normal" than high and did not necessarily decrease after removal of the tumour and clinical improvement.
B. IGF-I: IGF-I1 Ratio An explanation of this paradox came with the demonstration by Teale and Marks52 that whilst plasma IGF-I1 levels were either "normal" or only slightly elevated in these patients, plasma IGF-I levels were invariably very low. The plasma IGF1I:IGF-I ratio in the patients was sufficiently high and different from that in all other conditions examined, except sepsis and cachexia, to be diagnostically useful. Scrutiny of other cases published in the literature and in which appropriate analytical and clinical details are given7,8,50,51,53,76 leads us to believe that whilst not necessarily an invariable finding in all patients with tumour-induced hypoglycaemia, an abnormally low IGF-1:IGF-I1 ratio is extremely common and of pathogenic signifi~ a n c e .The ~ ~ IGF-1:IGF-I1 ratio is restored to normal following successful removal of the tumour; plasma IGF-I1 levels fall, even if they were not abnormally high pre-operatively; and IGF-I levels rise. The growth hormone response to hypoglycaemia returns and the concentration of the major plasma IGF binding protein (IGFBP3) rises to exceed, in molar terms, the combined concentration of IGF-I and IGF-II.92 We believe that the initial factor in the pathogenesis of tumour-induced hypoglycaemia is primary overproduction of IGF-I1 and that this in turn reduces growth hormone secretion in response to physiological stimulation. The "physiological" growth hormone deficiency so produced leads to reduced production and secretion by the liver of both IGF-I and IGF binding protein, and especially IGF-BP3, whose presence in the plasma normally reduces, if it does not remove entirely, the hypoglycaemic effect of both circulating IGF-I1 and IGF-I. The reduction in growth hormone-dependent IGF binding protein so produced allows more IGF-I1 to circulate in the plasma in the "free" or unbound form and be available for binding to insulin receptors on muscle and other peripheral tissues without
TUMOURS PRODUCING HYPOGLYCAEMIA
necessarily increasing its ”total” concentration in the plasma.
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by more recent explanations, very few, apart from the induction of stimulatory autoantibodies against the insulin receptor by lymphomas, adequately account for the clinical and laboratory C. Big IGF-11 and Other Possible findings. These are predominantly those of Mechanisms increased “insulin-like” action, i.e. non-ketotic An alternative hypothesis, not necessarily in fasting hypoglycaemia, with in many cases a very conflict with that outlined above, is that these high capacity for the removal of exogenous tumours produce an ”abnormal” or large IGFglucose. In some cases of tumour-induced hypog11. This, it is postulated, is more potent as a lycaemia, this equals the maximum rate achievable hypoglycaemic agent than regular IGF-I1 but with exogenous insulin infusion. Amounts of behaves in the same way in the i r n m u n ~ a s s a y . ~ ~ 500g of glucose a day are not uncommon. The Only further experience, characterization of the rate of glucose disappearance is not increased above normal following its rapid intravenous “large” IGF-11, and elucidation of its biological administration, nor would it be expected since it properties will resolve the problem. is the rapid rise in plasma insulin that occurs in Although most authors using modern analytihealthy subjects which is responsible for the rapid cal techniques, especially immunoassays, have assimilation of glucose administered in these found normal or raised IGF-I1 in patients harcircumstances. Such an insulinaemic response is bouring hypoglycaemia-producing tumours, Spaentirely lacking in patients with tumour-induced ~ ~ their own homologous radioredoni et t ~ [ .using hypoglycaemia, just as it is in many patients with ceptor assay for IGF-I1 based on human insulinomas. erythroleukemia cells (K562), however, have recently reported slightly reduced levels in one patient. Whether this was due to the method being unresponsive to the form of IGF-I1 circulating in X. LYMPHOMAS AND INSULIN this particular patient or indicative of a totally RECEPTOR ANTIBODIES different pathogenesis awaits further and more extensive experience with the assay. Hypoglycaemia has been recognized as occurStuart et aL7* attributed hypoglycaemia in a ring in patients with various types of lymphoma patient with colon cancer to a 3-to 5-foId increase for some 25 years.’,*O Very rarely it is a presenting in insulin receptor number. A more likely explafeature but more often it occurs only as a terminal nation is that the increased serum level of “nonevent. Hypoglycaemia is also a well-recognized suppressible insulin-like activity” or NSILP that complication of leukaemia in animals as well as they detected was a humoral factor with the in rare cases in human beings. Artifactual, postproperties of, or similar to, IGF-11. Plasma levels collection lowering of blood glucose concentration of IGF-I were very low. is difficult to exclude completely in these cases, Hypoglycaemia resulting from NICTH is not however. only associated with suppression of GH and Evidence for the existence and pathogenic insulin secretion in response to normally provocarole of stirnulatory insulin receptor antibodies in tive stimuli, but plasma glucagon is also low, hypoglycaemia caused by Hodgkin’s disease has though whether this has any role in the aetiology been produced by two groups of authors,’”,’’ but of the hypoglycaemia itself has not been deterdespite the passage of more than 4 years since mined. A similar depression of glucagon secretion these reports appeared, no other cases have been in response to hypoglycaemia is also observed in described to our knowledge. IGF-I1 was not patients with insulinoma. measured in either of these cases but in one Depression of growth hormone secretion, on IGF-I was measured (as somatomedin C by the other hand, is, we believe, of importance in incorporation of sulphur-35 into cartilage) and the genesis of NICTH, since it is largely or wholly said to be 75% of the reference range in one of responsible for the reduction in circulating IGFthem. Plasma growth hormone measured during BP3 that permits IGF-I1 to gain access to insulin spontaneous hypoglycaemia was 12.5 mU/1, which receptors on the tissues and can be reversed by is much higher than we and others have customexogenous GH administration. arily found in patients with IGF-I1 secreting Whilst none of the many explanations put tumours. It supports the idea that some other forward in the past to explain the aetiology of mechanism was involved. non-insulin-produced hypoglycaemia is ruled out
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It is of interest that in the seven or so patients with hypoglycaemia and lymphoma who were investigated by Gorden et plasma “IGF-like material”, measured by a radioreceptor binding assay and equating largely with multiplicationstimulating activity (MSA: now known to be identical with IGF-11), was distinctly low or very low compared with both a normal reference population and patients with other types of tumour associated with hypoglycaemia. The role of stimulatory insulin receptor antibodies in the pathogenesis of hypoglycaemia produced by diseases other than lymphoma has been established by various worker^^^,^^ and it is reasonable to assume that they may be involved in at least some of the very rare cases of lymphoma that are associated with hypoglycaemia.
XI. ADRENOCORTICAL TUMOURS AND PHEOCHROMOCYTOMAS
like other IGF-I1 secreting tumours as regards their ability to produce fasting hypoglycaemia. They produce reactive hypoglycaemia by an, as yet, unknown mechanism, but possibly involving either the release of catecholamines with stimulatory properties upon insulin secretion or with post-receptor effects. This may even be adrenaline itself working through P-adrenergic receptors. Episodic, probably stimulative, hyperinsulinism has been demonstrated in at least one pheochromocytoma case81in which fasting hypoglycaemia was not a feature. Very high plasma insulin levels (2081 and 174 mUA, respectively) were also found in the two out of ten patients8* who developed profound hypoglycaemia immediately after excision of a pheochromocytoma. Even in the remaining eight patients plasma insulin levels were abnormally high in relation to blood glucose when compared with those seen in other subjects who had undergone a similarly traumatic surgical experience.
A. Steroid-Secreting Tumours
XII. HEPATOMAS Hypoglycaemia secondary to adrenocortical tumours is rare but well recognized. Its pathogenesis is poorly understood. Almost all of the wellstudied cases were reported before the relevance of IGF-I1 was appreciated and the ability to measure it available. Nevertheless, it seems reasonable to assume that the large amounts of steroids, often of unusual nature, that these tumours produce are, in some way, involved in the pathogenesis of the hypoglycaemia.’ B. Catecholamine-Secreting Tumours
Fasting hypoglycaemia has been reported in association with malignant pheochromocytomas on a number of occasions.a Severe reactive hypoglycaemia during the course of prolonged oral glucose load tests, and which remitted completely after surgical removal of the tumour, has been reported even more frequently. Severe reactive hypoglycaemia has also been observed to occur immediately after removal of a pheochromocytoma.80-82 The cause of the hypoglycaemia is not necessarily, indeed it seems unlikely that it is, the same in each of these situations. In two patients with pheochromocytoma and fasting hypoglycaemia studied by Gorden et a1.,44 plasma levels of “IGF-like material” were modestly raised. Pheochromocytomas may, therefore, be
Hypoglycaemia attributable to hepatoma was described even earlier than that due to other tumour types but the only large series of cases that have been described are from the Far East.53, 83,84
Two types of hepatoma were distinguished by McFadzean and Yeunga4Type A, which is by far the commonest, is rapidly growing, poorly differentiated, and associated with rapid wasting and muscular weakness. Type B, which is slow growing and histologically well differentiated, is found in patients who appear well nourished but whose requirements for glucose to overcome their hypoglycaemia-which is an early feature of the condition-is prodigious. Some patients require up to 1500 g of glucose intravenously per day. In type A patients, hypoglycaemia is a terminal event and associated with cachexia. It is easily controlled by intravenous glucose. A somewhat similar distinction between two types of hepatoma was drawn by Wu et aLS3 who noted that those with hypoglycaemia tended to have higher plasma IGF-I1 and lower plasma IGFI levels than those without it. In a later paper, the same authors confirmed that although plasma IGF-I1 levels were not significantly higher in hypoglycaemic hepatoma patients than those who did not become hypoglycaemic, their plasma IGFI levels were lower.
TUMOURS PRODUCING HYPOGLYCAEMIA
A larger proportion of the IGF-I1 in the circulation of these patients was in the form of partially processed or “big” IGF-I1 than in normal subjects and they resembled, therefore, other patients with non-insulin hypoglycaemia-producing tumors. Plasma growth hormone responses to hypoglycaemia and other stimuli were not recorded.
XIII. HYPOGLYCAEMIA AND CANCER Hypoglycaemia may also occur as a terminal or agonal event, in addition to occurring as a dominant and comparatively “early” feature in rare cases of carcinoma developing outside the pancreas (especially of the stomach, caecum, and colon-though no tissue is exempt).12,13In some cases, this has been attributed to liver failure secondary to massive secondary invasion by the tumour. A more probable explanation is overwhelming production of Tumour Necrosis Factor (TNF) or cachectin by the tumour. This cytokine not only produces marked catabolism, but also profound hypoglycaemia, probably by inhibiting glucone~genesis.~~ A similar mechanism involving production of TNF is probably also responsible for the hypoglycaemia of septicaemia and overwhelming infection or infestation such as with malaria parasites.
XIV. DIAGNOSIS OF TUMOURINDUCED HYPOGLYCAEMIA The diagnosis of hypoglycaemia commences with its recognition as the cause of a patient’s symptoms and proceeds through the differential diagnosis to the cause upon which rational treatment depends. Only the differential diagnosis of fasting hypoglycaemia will be considered here. A. Insulinoma Inappropriate, rather than excessive, secretion of insulin and proinsulin is the hallmark of hypoglycaemia-producing pancreatic endocrine tumours. It is easily established in the vast majority of cases by demonstrating inappropriately high plasma insulin, proinsulin, and Cpeptide levels in peripheral venous blood whilst the patient is fasting and hypoglycaemic. Typically all three are abnormally high for the blood glucose
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concentration but only in a proportion are plasma insulin and C-peptide levels high in absolute terms when compared with a healthy overnight fasting norrnoglycaemic p o p ~ l a t i o n . ~ ~ , ~ ~ The situation is different in respect of proinsulin, whose concentration in plasma is generally high both in relative and in absolute terms. Data collected from the literature are confusing on this point mainly, we suspect, because of the difficulty, until recently, of measuring proinsulin (and proinsulin-like components) in plasma a c c ~ r a t e l y . ~ ~ , ~ ~ There was no universal standard of proinsulin available. Most authors expressed their results as percentages of immunoreactive insulin attributable to proinsulin and insulin respectively and this is unsatisfactory. With the advent of more accurate, specific, and precise assays directly applicable to plasma, several groups have reported absolute hyperproinsulinaemia in 90-100% of insulinoma patient^.^^,^^ Others have reported a slightly lower incidence of positive results,88 but whether this reflects methodological or genuine differences between populations awaits further evidence. Although hyperproinsulinaemia is not pathognomonic of any single condition, its presence in a patient with a history suggestive of spontaneous hypoglycaemia is very strong presumptive evidence of an insulinoma and its absence makes the diagnosis very unlikely, though one of adult nesidioblastosis is seemingly not ex~luded.~’ Because it is unnecessary to have the patient actually hypoglycaemic at the time a sample of blood is collected in order for a plasma proinsulin assay to be susceptible to interpretation, it is likely that this assay will replace relatively nonspecific immunoreactive insulin assays (IRI) as the first line of investigation in patients suspected of harbouring an insulinoma. Unless, or until, plasma proinsulin measurements in the presence of fasting hypoglycaemia do establish themselves as the gold standard, it will still be necessary to prove both: (1) Whipple’s triad of symptoms due to demonstrable hypoglycaemia during fasting that are relieved by intravenous glucose; and (2) inappropriately high peripheral plasma immunoreactive insulin and C-peptide levels in the presence of hypoglycaemia before a pre-operative diagnosis of insulinoma can be made with certainty. We do not recommend, either from our own laboratory experience or from the literature,
88
MARKS AND TEALE
calculation of a g1ucose:insulin ratio which is method-dependent and scientifically spurious, Instead, we believe that a reference range for plasma insulin, proinsulin, and C-peptide concentrations in the presence of hypoglycaemia must be established against which those obtained in patients can be assessed. C-peptide suppression tests where C-peptide acts a s a surrogate for endogenous insulin have enjoyed some p o p ~ l a r i t yThey . ~ ~ are, however, no more than screening tests capable of reducing to a manageable size the number of patients it is necessary to subject to rigorous exercise tests or admit to hospital for prolonged fasting in order to establish the diagnostic criteria of endogenous hyperinsulinism. None of the many stimulation tests that have been advocated over the past half-century and are sometimes still used add very much to the .~~ diagnosis of endogenous h y p e r i n s u l i n i ~ mTheir use should probably be confined to research or where facilities for C-peptide and proinsulin assays are not available. B. Non-insulin-Secreting Tumours
Non-insulin-secreting tumours do not often present difficulties in diagnosis once they have been suspected. They can nearly always be localized either clinically or radiologically. Plasma insulin, C-peptide, and proinsulin levels are always depressed in the presence of hypoglycaemia and measurement of plasma IGF-I, IGF-11, and their binding proteins usually clinches the diagnosis of an IGF-I1 secreting tumour. Typically IGF-I levels are very low, IGF-I1 levels are normally high and IGF-binding-protein 3 low to very low.52,91,97 In cases where this is not so, it may be worth looking for insulin-receptor binding a n t i b ~ d i e s In . ~ others, ~ measurement in urine of adrenal steroid metabolites or those of adrenaline may be worth undertaking.
XV. TREATMENT
Treatment of tumour-induced as in ail types of hypoglycaemia can be divided into two phases: palliation of the acute episode and definitive treatment directed at the cause. In the case of benign insulin-secreting tumours, surgical ablation of the adenoma is the treatment of choice and is extremely although very long-term follow-up93does suggest
an increased incidence of neuropsychiatric aberration, peptic ulcer disease, and NIDDM. In malignant tumours, ablation of the primary tumour is often worthwhile-even if hepatic metastases are present-as i t may produce relief from hypoglycaemia for a variable period. Drug therapy with a combination of diazoxide and a diuretic thiazide, both to augment the hyperglycaemic properties and to counteract the fluidretaining properties, is often remarkably effective in relieving the hypoglycaemia even of widely metastasized tumours. Tumoricidal therapy with streptozotocin and other agents is sometimes beneficial, as is hepatic artery thromboembolization, which may produce remissions lasting a year or more, and be repeatable if and when relapse occurs. Long-acting and synthetic somatostatin preparations have been used with varying success. They may both improve94 and worsen95 the hypoglycaemia, though improvement is probably the commoner. Patients with non-insulin-producing tumours (NICTH) undergo complete remission following surgical removal of the tumour in the rare cases where total ablation is possible. In many malignant or locally invasive tumours, alleviation of the hypoglycaemia often follows partial removal. In general, though not invariably, hypoglycaemia recurs as the tumour re-establishes itself. Diazoxide-chlorothiazide treatment is sornetimes effective in alleviating the hypoglycaemia but much less predictably than with insulinomas. Growth hormone has been used with great and seemingly specific in cases where primary overproduction of IGF-I1 was responsible for the hypoglycaemia. The effect is thought to be mediated by an increase in the release of growth hormone-dependent IGF binding protein (IGF-BP3) by the liver in response to exogenous growth hormone.” Failure to observe a sustained beneficial effect of exogenous GH after an early favourable response has also been reported, and may have been due to the relatively low dose of GH used and the development of GH-specific antibodie~.~~ Treatment with anti-inflammatory agent or immunosuppressive agent is worthy of trial in cases where insulin antibodies are implicated in the pathogenesis of hypoglycaemia, as it may produce prolonged remissions in cases with a non-tumorous a e t i ~ l o g y . ~ ~
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