Endocrine-Related Cancer (1998) 5 111-129 Tumours producing hypoglycaemia

V Marks and J D Teale

European Institute of Health and Medical Sciences, University of Surrey, Guildford GU2 5RF, UK and Department of Clinical Biochemistry and Nutrition, Royal Surrey County Hospital, Guildford GU2 5XX, UK (Requests for offprints should be addressed to V Marks)

Introduction Classification of hypoglycaemia- Hypoglycaemia is one of the commonest of medical producing tumours emergencies, mainly due to its high frequency as a Tumours producing hypoglycaemia can, broadly complication of insulin therapy of diabetes. It sometimes speaking, be divided - on the basis of the mechanism by arises, however, ‘spontaneously’ as a manifestation of which they most commonly produce hypoglycaemia - other diseases. The present review deals exclusively with into: (1) insulin-secreting tumours; (2) non-islet cell hypoglycaemia caused by neoplastic disease. (insulin-like growth factor-II (IGF-II)-secreting) tumours; For a very brief period, between 1927 and 1930, (3) myeloma, lymphoma and leukaemia; and (4) meta- tumours capable of producing hypoglycaemia were static neoplasia. thought always to secrete insulin and arise exclusively Hypoglycaemia produced by tumours other than within the pancreas. In the intervening years it has become insulinomas is usually referred to as ‘non-islet cell tumour increasingly apparent that almost any type of neoplasm hypoglycaemia’ (NICTH) and has more than one cause. can cause hypoglycaemia through a number of different mechanisms (Marks & Rose 1964, Laurent et al. 1971, Pancreatic endocrine tumours Daughaday 1989, Fajans & Vinik 1989). Insulin-secreting tumours are the commonest hormone- producing neoplasms of the gastrointestinal tract. They Symptomatology occur with an incidence of between 0.5 and 1 per million of the population per year (Kavlie & White 1972, Hypoglycaemia may be the presenting symptom of a Atkinson et al. 1981, Cullen & Ong 1987, Watson et al. tumour, a terminal epiphenomenon or anything in 1989). More than 80% are solitary benign adenomas, between, but is always rare. It is usually episodic and composed mainly or exclusively of morphologically provoked by fasting rather than reactive to the ingestion of normal B-cells. About 10% are metastatic, i.e. malignant, food. The one notable exception is hypoglycaemia due to whilst a further 10% are multiple but behave as benign. pheochromocytoma which may be of either variety Women outnumber men in the ratio of 6:4 for benign (Gorden et al. 1981, Hiramatsu et al. 1987, Paineau et al. but not for malignant insulinomas. The highest incidence 1988, Akiba et al. 1990). is in middle aged adults, though both benign and Symptoms of acute neuroglycopenia, character- malignant insulinomas have been observed very rarely in istically associated with insulin overdose, are unusual in children and in the very elderly. tumour-induced hypoglycaemia. Instead there is a gradual loss of cognitive function associated with diminished Insulin-secreting tumours motor activity, lethargy, the onset of somnolence and a Clinically significant insulinomas are generally between gradual drift into stupor or coma. Recovery may occur 10 and 20 mm in diameter at the time of diagnosis, spontaneously at any time but is hastened by the ingestion although tumours as large as 150 mm or as small as 5 mm of carbohydrate by mouth or the injection of glucose or in diameter have been found during surgery. Occasionally glucagon. very small tumours are overlooked at operation and found Biochemically, tumour-induced hypoglycaemia is only after very thorough histopathological examination of usually associated with hypoketonaemia (<300 µmol/l) the resected pancreas, or not at all. unlike that of most other types of ‘spontaneous’ hypo- In fewer than 5% of cases of true hyperinsulinaemic glycaemia apart from insulinoma (Teale et al. 1987). Only hypoglycaemia can no tumour be found. Whilst some of rarely are patients desperately ill in between hypo- these may be due to a small tumour being overlooked glycaemic episodes except when it is a terminal event in either at operation or at autopsy others are due to a patients with liver metastases. functional abnormality of the B-cells similar to that

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia causing persistent hyperinsulinaemic hypoglycaemia of Attempts to classify insulinomas into prognostically infants (PHHI) which may, or may not, manifest itself useful histopathological categories have been made for 60 histologically as islet hyperplasia (nesidioblastosis). This years or more with little success (Graeme-Cook et al. condition must be distinguished from the nosologically 1990). It became apparent soon after their initial distinct condition of microadenomatosis which can occur identification that classical morphological and histo- either as an isolated histopathological finding or as part of logical criteria were of little value for distinguishing multiple endocrine neoplasia type I (MEN-I) (Diarmuid et malignant from benign tumours. Only the presence of al. 1994). metastases, or their subsequent appearance, could be The natural history of insulinomas (Marks 1991) relied upon to make the distinction. suggests that apart from their propensity for causing Creutzfeldt and co-workers (1973) classified insulin- hypoglycaemia - from which death is fortunately very omas into four types on the basis of their histological, rare - they produce no adverse effects. Specifically they ultramicroscopic and immunocytological appearances. appear not to cause obstruction to the hepatic or pancreatic Type 1 is the commonest and accounts for almost half ducts or to undergo malignant transformation. There are of the cases. In this type, virtually every cell contains many reports, especially in the older literature, of typical β-granules. symptoms attributable to hypoglycaemia due to Type 2, the second commonest, accounts for 25% of insulinoma extending over a period of 25 years or more the cases. Most of the cells contain a number of atypical before its true cause was identified and removed (Fonseca granules - demonstrably different from those of normal A, et al. 1989). B, D or PP cells - in addition to typical β-granules. The The average time between onset of symptoms and atypical granules resemble the coated β-granules that are diagnosis of its cause as due to insulinoma is now about found in small numbers in normal B-cells and within 1 year. Delay, when it does occur, is almost always the which proinsulin is believed to be converted into insulin consequence of reluctance by the patient to seek help, or and C-peptide (Orci et al. 1988). failure of the practitioner to suspect hypoglycaemia. Once Type 3 tumours consist solely of cells containing suspected, diagnosis of insulinoma seldom presents any atypical β-granules. None contains typical ones. Though real difficulty (Marks & Rose 1981, Marks 1991, Marks & not specifically identified as such, these probably Teale 1996, Marks 1997, Nauck et al. 1997). correspond to predominantly, or exclusively, proinsulin- Insulinomas are distributed evenly throughout the secreting tumours (proinulinomas). pancreas and only very rarely ectopically (2%). In this Type 4 tumours included the only two metastatic respect, as in the relative infrequency of their malignancy, carcinomas in the Creutzfeldt series. None of the four insulinomas differ from other hormone-producing tumours so classified had any of the characteristic histo- tumours of the gastrointestinal tract. logical features of an insulinoma. All gave negative The commonest ectopic sites are the duodenum and reactions with classical histological and immunocyto- the immediate vicinity of the pancreas, but less than 1% of chemical stains. They all showed ultramicroscopic signs the 677 insulinomas collected from the literature by of high functional activity. Tumours of this type would Laurent and co-workers prior to 1971 were located outside possibly, in former times, have been classified as the pancreas. Only a tiny number of ectopic tumours have carcinomas of unknown origin or carcinoids rather than been reported in recent years (Yoshikawa & Wakasa 1980, ‘insulinomas’, even in experienced histopathological Miyazaki et al. 1986). laboratories. Insulinoma histology Many insulinomas are composed Berger and co-workers (1983) classified hypo- entirely of seemingly normal B-cells. More thorough glycaemia producing tumours of the pancreas on their examination, especially by electron microscopy and functional rather than histological characteristics. immunocytochemistry, usually reveals a small but Group A tumours were characterised by the almost variable number of other pancreatic endocrine cell types, complete suppressibility of insulin and proinsulin of which somatostatin-containing D-cells are the secretion by both diazoxide and somatostatin. Histo- commonest. logically they were characterised by an abundance of Insulinomas show variable and unpredictable staining well-granulated B-cells in a trabecular arrangement. with traditional as well as with immunohistological Group B tumours resisted the suppressant effects of reagents, including synaptophycin, neuron-specific diazoxide and somatostatin and their cells were arranged enolase and chromogranin, which have been used as in a ‘medullary pattern’ and contained fewer less well general markers of neuroendocrine tumours or tumours of granulated β-granules. amine precursor uptake and decarboxylation cells Only 20% of circulating total immunoreactive insulin (APUDomas). Some stain very poorly or not at all even (IRI) was proinsulin and proinsulin-like components in with anti-insulin antisera. group A patients, which is not very dissimilar to that of

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Endocrine-Related Cancer (1998) 5 111-129 normal subjects. In group B patients on the other hand they late in life and long after the initial histological diagnosis accounted for 50% or more of total IRI. The difference has been made. reflects the smaller proportion of coated to uncoated Functional transformation from a pancreatic endocrine β-granules in the group A patients. tumour manifesting features of a ‘glucagonoma’ into an Despite their sophistication compared with previous ‘insulinoma’ and vice versa has been described. So too classifications, neither the Creutzfeldt nor Berger classi- have manifestations of ectopic hormone production which fications enables a prognostically important distinction to are more often seen with other types of pancreatic be made between malignant and non-malignant tumours. endocrine tumour most of which are malignant. Among Nor, for that matter (Graeme-Cooke et al. 1990), does the the most common syndromes associated with ectopic observation that malignant, but not benign, insulinomas hormone production by insulin-secreting carcinomas of express - and sometimes secrete - the subunits of human the pancreas are Cushing’s syndrome, Zollinger-Ellison chorionic gonadotrophin which had originally appeared to syndrome, hypersomatostatinaemia, acromegaly, carcin- offer this possibility. oidosis, and goitre and hypercalcitoninaemia (Laurent et Confusion between malignant insulinomas mas- al. 1971, Wright et al. 1980, Marks & Rose 1981, Bugalho querading as metastatic carcinoids may, and sometimes et al. 1994). does, occur. This is less likely to occur if immuno- Metastatic insulinomas and mixed islet cell tumours staining with insulin antisera is carried out routinely on all vary in their aggressiveness (Ericksson et al. 1989). Pro- pancreatic carcinoids since symptoms from hypogly- gression, from the first appearance of symptoms to death caemia are not inevitable until quite late in the course of from inexorable hypoglycaemia can occur in 6 months or the disease (Marks 1995). less unless effective antihypoglycaemic treatment with Amyloid A substance with the histological appearance of diazoxide plus chlorothiazide, surgical ablation (de- amyloid was recognised as being deposited in varying bulking), chemotherapy, hepatic artery embolisation, or amounts in insulinomas whether benign or metastatic long cryotherapy either alone or in combination, can be before it was isolated and characterised chemically achieved (Valette & Souquet 1989, Wells et al. 1990, (McIntyre 1989, Porte & Kahn 1989, O’Brien et al. 1994). Krentz et al. 1996). Islet amyloid polypeptide (also known as amylin) is a 37 Providing hypoglycaemia can be prevented, good amino acid polypeptide which is co-secreted with insulin quality-of-life with survival (for 10 years or more) can from both normal and diseased B-cells. It may be co- occur since these tumours, though malignant, are often deposited with the pentomeric amyloid protein (pentraxin) very slow growing and do not produce the typical features common to all varieties of amyloid in the islets of patients of metastatic disease such as anorexia, nausea and loss of with non-insulin-dependent diabetes mellitus (NIDDM) body weight until late in the course of the disease. as well as in patients with pancreatic endocrine tumours (Crowley et al. 1996), though it is rare in all except Aetiology of pancreatic endocrine tumours insulinomas. Most insulinomas occur sporadically, a further 5-10% as It has been suggested that amylin might be of part of the MEN-I syndrome (Diarmuid et al. 1994, pathogenic importance in the aetiology of NIDDM. It is Thakker 1997). An association with NIDDM has been now known, however, to be co-produced and co-secreted suggested on the basis of a small number of family studies with insulin by normal as well as by insulinoma B-cells but a link has not been established (Service et al. 1976). and those of patients with NIDDM. It is still unknown, A relative insensitivity to exogenous insulin is often however, why islet amyloid polypeptide should be observed in patients harbouring insulinomas and generally deposited in large amounts in some insulinomas but not in attributed to, though far from established as due to, ‘down others, nor whether it has any prognostic significance. It regulation’ of insulin receptors (Nankervis et al. 1985, does not occur in children with (familial) PHHI (Rother et McGee et al. 1987, de Kreutzenberg et al. 1994). It has al. 1995), which, in its nosology at least, resembles long been known to persist after successful removal of the insulinoma. tumour and abolition of hypoglycaemia, and in a minority of cases insulin manifests itself as impaired glucose Mixed cell tumours and carcinoids tolerance or even frank diabetes. While this may be While most benign insulinomas contain isolated D and/or secondary to damage done to the pancreas during A cells, their presence in greater numbers is usually resection of the tumour (Dunn 1971) it may also be due to associated with malignancy, i.e. metastasising tumours. persistence of a primary defect in peripheral insulin Metastatic islet cell tumours often resemble carcinoids sensitivity (de Kreutzenberg et al. 1994) similar to that histologically and may be reported as such unless special seen in patients with NIDDM. staining techniques are used. They may be associated with It is probably no coincidence that no example of a no evidence of endocrinological disturbance until quite benign insulinoma developing in a patient with type I

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia diabetes (insulin-dependent diabetes mellitus (IDDM)) by the brain and other obligatory glucose using tissues has ever been reported, in contrast to patients with type II (Marks & Rose 1981). diabetes (NIDDM) in whom it occurs with possibly an It is the inability of insulin-secreting tumours of the even greater frequency than in the general population pancreas to shut down their insulin secretion in response (Heik et al. 1988, Grunberger 1993). A contrary view has to hypoglycaemia, whether induced by fasting or exo- been expressed by Kane et al. (1993) who found pre- genous insulin, that is their biochemical hallmark. This existing diabetes in only 1 of their series of 313 patients anomaly occurs only very rarely in other disorders, most with insulinoma, making it a very rare occurrence indeed. notably PHHI or ‘nesidioblastosis’ and sulphonylurea A case of malignant insulinoma has, however, recently overdose (Teale et al. 1989). been reported in a patient with incontrovertible type I Though insulinoma B-cells may be functionally diabetes (Svartberg et al. 1996). abnormal in other ways, none is as uniformly present as failure to suppress insulin secretion in response to hypo- MEN-I glycaemia. Most respond poorly, if at all, to the insulino- Insulinomas are the commonest manifestation of MEN-I trophic effects of hyperglycaemia per se (produced by after parathyroid and pituitary adenomas. They do not intravenous glucose for example) and do not exhibit a first occur in the other varieties of multiple endocrine adeno- phase insulin response to intravenous glucose. matosis, i.e. MEN-IIa and -IIb. The familial occurrence of They do, on the other hand, generally respond seemingly solitary insulinomas (Maioli et al. 1992) has normally or excessively to glucagon and other insulino- been reported on several occasions, but whether this trophic enteric hormones (gastric inhibitory peptide and represents a forme-fruste of MEN-I (Diarmuid et al. 1994) glucagon-like peptide-I (GLP-I)) that are released into the or a specific abnormality awaits gene analysis of affected blood following ingestion of a meal. This may account for individuals (Larsson et al. 1988). the rare examples of insulinoma that present with a history Hyperinsulinaemic hypoglycaemia in children and of reactive rather than of fasting hypoglycaemia. young adults is particularly likely to be due to either The insulinotrophic amino acid L-arginine generally MEN-I or to the persistent functional hyperinsulinism of produces a normal insulinaemic response in insulinoma infancy, formerly referred to as nesidioblastosis (Mathew patients. This is in contrast to L-leucine which - whether et al. 1988, Losada et al. 1995). In children below the given orally or intravenously - often provokes excessive age of 4 years the histopathological features of solitary insulin secretion and precipitates hypoglycaemia. A insulinomas removed at operation resemble those of similar response is observed only in patients with the ‘nesidioblastosis’ more closely than those of solitary leucine-sensitive variety of PHHI and normal subjects benign insulinomas in adults. pretreated with sulphonylureas. Insulinomas may respond to hypercalcaemia by Chemical pathology secreting insulin in amounts sufficient to produce hypo- Insulin Spontaneous hypoglycaemia was believed from glycaemia. Advantage has been taken of this fact -like that the time of its first description as a clinical entity, until the of other insulin secretagogues, such as tolbutamide and introduction of radioimmunoassays for insulin in blood, to glucagon - in the diagnosis of insulin-secreting tumours. result from overproduction of insulin by an insulin- All such tests are of limited diagnostic use because of secreting tumour similar to that of thyroxine in thyro- their low predictive value. They are most useful toxicosis rather than, as is now quite apparent, from its (Doppman et al. 1995) when employed in conjunction inappropriate rather than excessive secretion (Samols & with percutaneous trans-hepatic catheterisation for pre- Marks 1963). operative localisation, should this be considered Normal glucose homeostasis depends, in large part, necessary, of insulinomas already diagnosed by more upon the ability of the very modest fall in blood glucose reliable methods. concentration produced by fasting to below a pre- Proinsulin Proinsulin ordinarily constitutes a higher determined ‘set’ to suppress endogenous insulin secretion. proportion of circulating total IRI in patients with The suppression is not ordinarily complete, however, insulinomas than in healthy people, especially in patients (unlike in IDDM) so that although peripheral glucose- harbouring malignant tumours (Samols 1965, Hayashi et dependent tissues no longer abstract glucose from the al. 1977, Cohen et al. 1986, Cohen & Camus 1988, glucose pool, lipolysis in adipose tissue and glycogen- Hampton et al. 1988, Hale et al. 1991, Marks et al. 1992, olysis in the liver is not sufficiently disinhibited as to Tasaka et al. 1993, Gorden et al. 1995). It is still unclear permit rampant ketosis and hyperglycaemia. Instead whether this is a consequence of the neoplastic process or plasma ketones (and non-esterified fatty acid (NEFA) a factor in its aetiology, as it might be if the propensity to levels) rise only modestly and net glucose production by develop an insulinoma is greater in people with a the liver (appearance) is constrained to match utilisation predisposition to NIDDM.

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Rarely, benign tumours have been found that secrete Marks & Rose 1981). It is now recognised that in most proinsulin as their main (Alsever et al. 1975) or even sole cases it is a consequence of overproduction of an aberrant insulin-like product, leading to the suggestion that they form of IGF-II (Megyesi et al. 1974, 1975, Gorden et al. should be called ‘proinsulinomas’ (Cohen & Camus 1981, Axelrod & Ron 1988, Ron et al. 1989, Lowe et al. 1988). 1989, Shapiro et al. 1990, Teale & Marks 1990, In one such case, recently studied by us, all of the very Daughaday & Trivedi 1992). Other, even rarer causes, are small amount of circulating insulin appeared to derive sometimes encountered, however, and these will be from the normal islets and it responded to insulinotrophic discussed later. stimulation with glucose, glucagon etc. and to suppression by octreotide, whereas the proinsulinoma itself did not. Histological classification Though fibromas and fibrosarcomas are probably the best Non-pancreatic tumours known example of tumour-producing NICTH, no histo- In 1929 Nadler and Wolfer published a case of hypo- logical type of tumour is exempt. Hypoglycaemia, once glycaemia associated with primary carcinoma of the liver. manifest, is usually both profound and relentless. It may, One year later Doege described a patient with episodes of however, respond to surgical ablation or debulking of the altered consciousness from whom he removed a large tumour - at least temporarily. Surprisingly hypoglycaemia mediastinal tumour. The significance of the symptoms does not always reappear even if the tumour recurs and was not appreciated, however, until some 3 years later grows to its former size. when they recurred and were shown to be of hypo- In patients who present with NICTH the anamnesis is glycaemic origin (Marks & Rose 1964, Laurent et al. similar to that of insulinoma. Differentiation is, however, 1971). easily made on the basis of plasma hormone assays (Marks More cases of hypoglycaemia occurring in association & Teale 1996). Unlike insulinoma, in which hypo- with hepatic and other types of carcinoma, or with glycaemia is always the presenting symptom, in NICTH mesenchymal tumours, were described over the years, in the diagnosis of neoplasia may already have been made by which it was the presenting or dominant feature of the the time hypoglycaemia appears. patient’s illness. In others it occurred only as a terminal NICTH is not necessarily an indicator of size or event. invasiveness of the tumour, though fibromas and fibro- Hypoglycaemia of both types is referred to, through- sarcomas are invariably large or very large by the time out the rest of this article, as NICTH and has many causes. they manifest it. Only very rarely do such tumours weigh less than 500 g and most weigh between 2 and 4 kg. The Types of tumour largest so far recorded weighed over 20 kg. Most are in the The association that has attracted most interest has been thorax or in the retroperitoneal space and may, despite that between hypoglycaemia and large fibrosarcomas, their large size, have been clinically silent. usually of low or moderate malignancy, arising in the Other tumours of a special interest because of their thorax or retroperitoneal space. Hypoglycaemia is, how- association with hypoglycaemia are hepatomas, haem- ever, rare even in them. In one large series of cases angiopericytomas, pheochromocytomas, adrenocortical (England et al. 1989) only 3% with benign and 11% with adenomas and carcinomas, myelomas, lymphomas and malignant fibromatous tumours developed hypo- leukaemias. Even tumours of the meninges have been glycaemia at any time in their evolution. Apart from described as causing NICTH (Ferguson & Flinn 1995, hepatomas the proportion of epithelial tumours mani- Phuphanich et al. 1995) and it would appear reasonable to festing hypoglycaemia is even smaller, probably less than assume that no type of tumour is exempt (Table 1). 0.1%. Craniopharyngiomas, pituitary adenomas and tumours The true incidence of tumour-induced hypoglycaemia of the brain that have been treated by irradiation may cause is, however, difficult to ascertain and no population study hypoglycaemia secondary to hypopituitarism - usually as comparable with those for insulinoma has been published. a late phenomenon but occasionally as the presenting In our own experience of cases of hypoglycaemia referred symptom. They will not be considered here. for diagnosis from all over Britain, NICTH is about one- quarter (25%) as common as insulinoma but this is Chemical pathology of NICTH probably an underestimate. Many cases undoubtedly go Despite a few early reports of dubious authenticity in unrecognised especially in patients with metastatic which insulin was claimed to be the causative agent disease. (Pavelic & Popovic 1981, Baltic et al. 1985) NICTH is The cause of NICTH was, from the time of its now known not to be caused by insulin. Indeed, doubt has discovery until comparatively recently, the subject of been expressed as to whether ectopic insulin production intense speculation (Field et al. 1963, Laurent et al. 1971, has ever been demonstrated in a tumour that was not of

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partially resolved but still account for some of the Table 1 Histological classification of 68 consecutive difficulties experienced by authors using poorly validated tumours producing NICTH through overproduction of assay techniques. IGF-II investigated in Guildford. The commonest cause of NICTH is undoubtedly the overproduction of an aberrant form of IGF-II (Daughaday Histology Number 1997). Most, if not all of the other biochemical effects that Carcinoma 31 are observed, such as suppression of insulin, glucagon, Lung 7 growth hormone (GH) secretion and depression of Pancreas 6 circulating NEFA and ketone levels, stem from this. Stomach 5 There are, however, other rare causes of NICTH such Undifferentiated 3 as autoantibodies to the insulin receptor, overwhelming Adrenal 2 metastatic destruction of the liver and the production of Kidney 2 tumour necrosis factor (TNF) and other hypoglycaemic Oesophagus 2 Ovary 1 cytokines, and these are considered later. Prostate 1 IGF-I and IGF-II Description of the IGFs, their isolation, Breast 1 nomenclature and full range of biological properties is Larynx 1 beyond the scope of this review (Froesch et al. 1963, Jacob et al. 1968, Froesch & Zapf 1985, Clemmons 1989). So Sarcoma/fibroma 23 too is discussion of the IGF-binding proteins (IGFBPs) Fibroma 6 (Baxter & Martin 1989, Baxter et al. 1995, Baxter 1996) Mesothelioma 5 Fibrosarcoma 4 of which at least six types have been identified in plasma Haemangiopericytoma 4 and possibly a seventh. Neurofibroma 1 The IGFs were identified by their ability to mimic the Leiomyosarcoma 2 effects of insulin upon isolated tissues in vitro in the Sarcoma of kidney 1 presence of neutralising anti-insulin antibodies. Together, the two IGFs account for most of the biological activity Hepatoma 4 described in the older literature as non-suppressible insulin-like activity. Carcinoid/neuroendocrine 1 Both IGF-I and IGF-II are structurally similar to Unknown 9 proinsulin. Immunologically they differ both from it and from one another. Immunoassays have been developed for each of the IGFs with little or no cross-reactivity between ‘pancreatic’ origin. The few cases of ectopic insulin them and none at all with proinsulin. Clear separation of production extant in the literature have usually either the three chemical species was, however, not possible with been metastatic APUDomas (Sasaki et al. 1980) possibly earlier bio- and radioreceptor assays and this may explain of pancreatic origin, or are insufficiently well documented some of the confusion found in the older literature to substantiate the claim that they were insulin or pro- surrounding investigations into the aetiology of NICTH. insulin producing. A very recent case of cervical cancer Both IGF-I and IGF-II circulate almost completely investigated by us is a possible exception since it produced (>90%) bound to specific IGFBPs. This is in complete insulin, C-peptide and proinsulin in prodigious amounts. contrast to insulin and proinsulin for which there are no In an otherwise typical case of NICTH described by Lyall specific binding proteins. et al. (1975) plasma insulin levels were both absolutely The two IGFs bind with more or less equal avidity to and inappropriately high during hypoglycaemia prior to each of the IGFBPs. The complex formed associates with removal of a 680 g thoracic neurofibrosarcoma but an acid-labile subunit (ALS) to make a ternary complex. returned to normal post-operatively with restoration of This has a molecular mass in the region of 150 kDa, which normoglycaemia. The tumour contained no secretory virtually confines it to the intravascular compartment. In granules and extracts of it contained no insulin. The normal healthy subjects the total concentration of IGF is, possibility that the tumour secreted an insulinotrophic in molar terms, equal to or slightly less than that of the substance cannot be dismissed. combined IGFBPs. The controversy as to whether NICTH is due to Production of the IGFBPs and their release into the overproduction of one or other of the two IGFs (IGF-I and circulation is determined by a variety of factors. IGF-II) or to some other substance with insulin-like Production of the most plentiful (IGFBP-3) is linked, in properties was largely a consequence of difficulties with some poorly understood way, to the production of IGF-I assay technology (Baxter 1990). These have now been itself. This, in turn, is linked to GH action on the liver.

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Though many, if not all, tissues, are capable of producing circulating amounts of IGFBP-3 and ALS is the main it, IGF-I in the circulation derives almost entirely from the reason that these tumours produce hypoglycaemia. They liver. The liver is also the main, if not sole, source of the do so by increasing the availability of ‘free’ IGF-II to bind IGFBPs. The origin of circulating IGF-II is seemingly not to IGF receptors - and possibly to insulin receptors - in the exclusively the liver. tissues. The normal molar ratio of IGF-II:IGF-I in plasma Immunoassay Immunoassays for plasma IGF-I have varies but is usually about 3:1. Their concentration, been used clinically for many years in the assessment of whether expressed in molar or mass units, is many malnutrition, for diagnosing and monitoring the response hundreds of times that of insulin (Table 2). They do not to treatment in acromegaly and to human growth ordinarily exert an insulin-like effect, however, either hormone (hGH) in hypopituitarism (Teale & Marks 1986). on blood glucose or NEFA levels because they are Clinical assays for IGF-II are, however, comparatively virtually excluded from contact with insulin and IGF new and still poorly validated (Baxter 1990). Most receptors on tissues due to their incorporation into the antisera fail to distinguish between regular IGF-II and the IGFBP/ALS/IGF ternary complex. This may explain why, larger molecular forms possessing the E-domain. This is despite their normal concentration in patients with ordinarily cleaved from proIGF-II during intracellular uncontrolled IDDM, IGFs exert no hypoglycaemic or processing but in NICTH there is a defect which leads to antilipolytic effect. the appearance in the plasma of a disproportionately large Big IGF-II The demonstration of increased amounts of amount of the uncleaved peptide. This is analogous to the the mRNA for IGF-II in tumour tissue taken from patients disproportionate ratio of proinsulin to insulin in the blood with hypoglycaemia-producing tumours established a role of most patients with insulinomas. for it in the pathogenesis of NICTH (Lowe et al. 1989, IGF-II:IGF-I ratio Teale & Marks (1990) were the first Shapiro et al. 1990). It was, however, only after radio- to draw attention to the distortion of the IGF-II:IGF-I ratio immunoassays for circulating IGF-I, IGF-II, and latterly, in patients with NICTH and suggest that it might prove the E-domain of the ‘large’ or aberrant form of IGF-II, useful in its diagnosis, especially in cases in which IGF-II became available (Perdue et al. 1991) that the key role of levels themselves were ‘normal’ or only slightly elevated. IGF-II in the pathogenesis of NICTH has been proved. Their early conclusions have been confirmed repeatedly Indeed the presence, in plasma, of increased concentration and a molar ratio of total plasma IGF-II:IGF-I of more of IGF-II, mostly of the ‘big’ but also the normal variety than 10 is virtually pathognomonic of NICTH. Apart from (Daughaday et al. 1988, 1990), coupled with a gross NICTH, abnormally high IGF-II:IGF-I ratios are found reduction in the amount of IGF-I is so characteristic of only in very rare cases of hypoglycaemia due to sepsis or NICTH that it is diagnostically useful (Teale & Marks cachexia, but in them the absolute amounts of IGF-II are 1990). generally subnormal as well as those of IGF-I. It has still to be determined whether the reduced Results in 50 consecutive patients with NICTH whose affinity of ‘big’ IGF-II for IGFBPs (Daughaday & plasma was assayed in Guildford are shown in Table 2. Kapadia 1989, Daughaday 1997) or the reduction in Twenty-eight patients were women and 22 men. Seventy-

Table 2 Diagnostic parameters in 50 consecutive cases of NICTH.

Control NICTH patients hypoglycaemic subjects*

Age (years) 16 ±15 (30-91) Glucose (mmol/l) 2.4±2.5 <3.0 Immunoreactive insulin (pmol/l) <25 Variable, depending on cause C-peptide (pmol/l) <75 Variable, depending on cause β-hydroxybutyrate (µmol/l) 143±151 >300** Growth hormone (mU/l) 4.6±6.2 >10* Total IGF-I (nmol/l) 5±2 18±14 Total IGF-II (nmol/l) 102±35 68±12 IGF-II:IGF-I molar ratio 21.8±10.7 3.8±1.5 ‘Big’ IGF-II (nmol/l) 20.1±6.0 9.8±2.0

* Including hyperinsulinism: iatrogenic and spontaneous. ** Excluding hypoglycaemia caused by hyperinsulinism: iatrogenic or spontaneous.

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia six percent were aged 60 or more, the youngest was 28 That this can be accomplished without a significant years old, the oldest 91. All had blood glucose levels increase in total plasma IGF-II was recently demonstrated below 2.2 mmol/l at some time in the course of their by Moller et al. (1996) in a case of NICTH in which ‘free’ illness, although only 44 patients were hypoglycaemic at IGF-II was increased 30-fold and ‘free’ IGF-I more than the time blood was collected for hormone assay. Plasma 4-fold despite an almost insignificant increase in total β-hydroxybutyrate levels were below 300 µmol/l in 37 of plasma IGF-II and an 85% reduction in IGF-I. the 42 patients in whom they were measured whilst Hypoglycaemia results from a combination of hypoglycaemic. In none did they exceed 600 µmol/l. decreased release of glucose into the blood by the liver and More than 50% of the tumours in which the histology grossly accelerated glucose utilisation by muscle and was known were of epithelial origin. Carcinomas of other tissues. In NICTH this can reach prodigious the lung and of the stomach were the most common proportions, much greater, for example, than is ordinarily (Table 1). encountered in insulinoma in which insulin resistance is a Other hormones Abnormalities of many other hormones common feature. concerned with glucose homeostasis are characteristic of The 3- to 5-fold increase in insulin receptor number in NICTH (Marks 1976). Plasma insulin, proinsulin and a patient with NICTH due to colon cancer described by C-peptide levels are invariably low during hypoglycaemia Stuart et al. (1986) was probably a result of ‘up- and do not respond normally to hyperglycaemia and other regulation’ of insulin receptors in response to suppressed insulinotrophic stimuli (Marks & Samols 1966). Plasma plasma insulin levels that are so characteristic of NICTH. GH levels are also low or very low during spontaneous This is, however, unlikely to be the explanation for the hypoglycaemia and this is thought to be due to a direct increased insulin sensitivity that was held to account for suppressant action of IGF-II on GH secretion. Patients the occurrence of (insulin-induced) hypoglycaemia in an with insulinomas may also have low plasma GH levels insulin-dependent diabetic patient after he developed a during spontaneous hypoglycaemia, but in them it is primary hepatoma (Barzilai et al. 1991) since in this thought to be secondary to hypothalamic adaptation to patient the sole source of insulin had been from a bottle. hypoglycaemia itself. Plasma glucagon levels are Similarly, in a case described by Sturrock et al. (1997), in invariably low in patients with NICTH and do not respond which the IGF-II:IGF-I ratio was high as a result of a normally to glucagonotrophic stimuli. This is unlike pancreatic carcinoma, spontaneous hypoglycaemia adrenaline, which responds normally to hypoglycaemia developed late in the course of her illness necessitating (Eastman et al. 1992), but too few patients have yet been discontinuation of insulin therapy. investigated to validate this conclusion. Non-insulin-dependent glucose uptake by the tumour itself, reflected in the hyperlactacidaemia often found in Pathophysiology of NICTH these cases, may also make a small contribution to the The initiating factor in NICTH appears to be primary hypoglycaemia but it is not, as was once thought, a key overproduction of predominantly ‘big’, but also of regular factor in its pathogenesis. IGF-II, by the tumour. Thereon the mechanism is The role of depressed counterregulatory hormone speculative. secretion presumably by IGF-II in NICTH is difficult to Our own view is that primary overproduction of assess. The hyperglycaemic response to exogenous IGF-II by the tumour leads to an increase in the glucagon is often exaggerated unlike the insulinaemic concentration of ‘free’ IGF-II in the plasma and a response, which is suppressed. Likewise exogenous GH secondary reduction in GH secretion. One consequence of may alleviate hypoglycaemia in NICTH without affecting this is reduced production and secretion by the liver of plasma IGF-II levels (Teale & Marks 1998). IGFBP - especially IGFBP-3, which is far and away the Unlike the counterregulatory polypeptide hormones, most plentiful and ‘GH-dependent’ - as well as of both adrenaline and nor-adrenaline secretory mechanisms IGF-I itself. There is also a marked reduction in circulating are said to remain intact in patients with NICTH (Eastman ALS. et al. 1992). The overall reduction in total IGFBPs - despite a notable and probably ‘compensatory’ increase in IGFBP-2 Associated conditions - permits more of the IGF-II to circulate in the ‘free’ or Laurent et al. (1971) drew attention to the high unbound form and consequently to a greater percentage of incidence (10%) of thyroid enlargement, with or without it becoming available for binding to IGF receptors - as thyrotoxicosis, in patients with NICTH and to its well as to insulin receptors with which it cross-reacts association with acromegaly. Skin tags, excessive oiliness (Fradkin et al. 1989) - and which are present on liver, of the skin and rhinophyma have also been observed muscle and all other peripheral tissues. (Trivedi et al. 1995), but whether these features, which are

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Endocrine-Related Cancer (1998) 5 111-129 characteristically associated with over- rather than under- Adrenocortical tumours and pheocromocytomas production of GH, are related to, and caused by, over- Steroid-secreting tumours expression of IGF-II activity is unknown. Adrenocortical tumours are a rare but well-recognised Coincidence of fibromas and insulinomas The co- cause of NICTH (Marks & Rose 1964, Laurent et al. incident presence of a large mesenchymal tumour capable 1971). The hypoglycaemia was, at one time, thought to be of producing NICTH in patients harbouring an a consequence of the secretion of abnormal steroids with insulinoma has been reported on several occasions both specific hypoglycaemic properties. This now seems before and after the advent of immunoassays capable of unlikely and, in two recent cases of our own, the chemical differentiating between them (Bruno & Ober 1962, pathology was no different from that of other IGF-II- Coskey & Tranquada 1964). Since neurofibromatosis has secreting tumours. Nevertheless it seems reasonable, until also been described in association with other types of proved otherwise, to assume that some of the unusual APUDoma the occurrence may be more than coincidental steroids these tumours produce may, in some way, (Fung & Lam1995). contribute to the production of hypoglycaemia - possibly by interfering with normal glucocorticoid production or Hepatomas action. Hypoglycaemia due to hepatoma was described soon after Catecholamine-secreting tumours that due to insulinoma and earlier than that from any other Both reactive and fasting hypoglycaemia have been type of non-islet cell tumour. Many of the large series of described in association with malignant pheochromo- NICTH due to primary hepatoma have emanated from the cytoma (Gorden et al. 1981). The cause is unlikely to be far east where hepatomas are common (McFadzean & the same in each of these situations. Yeung 1956, 1969) but it is also disproportionately Severe reactive hypoglycaemia in patients with a common in the USA (Wu et al. 1988, Shapiro et al. 1990) pheochromocytoma with remission following its surgical as well as in the UK. removal has been described on a number of occasions. It McFadzean & Yeung (1969) distinguished two types has also been reported as occurring for the first time of hepatoma causing hypoglycaemia: type A tumours, immediately following tumour excision (Hiramatsu et al. which are far the commonest, are rapidly growing, poorly 1987, Paineau et al. 1988, Akiba et al. 1990, Chiang et al. differentiated tumours that are associated with rapid 1993). The mechanism in such cases is unknown, but wasting and muscular weakness; type B tumours, which seemingly connected to the presence of excessive are slow growing, are histologically well differentiated catecholamine action either stimulating insulin secretion and occur in patients who appear to be well nourished. or through a post-receptor effect. In patients with type B tumours the requirement for Episodic, probably stimulative, hyperinsulinism has glucose to prevent hypoglycaemia can be prodigious, been demonstrated in at least one patient with reactive some patients requiring up to 1500 g glucose hypoglycaemia due to pheochromocytoma and in which intravenously per day. Type A patients, on the other hand, fasting hypoglycaemia was not a feature (Hiramatsu et al. require only very modest amounts of glucose to prevent 1987). hypoglycaemia, which is usually a terminal event Very high plasma insulin levels were found in two associated with cachexia. These patients correspond to out of ten patients (12 480 pmol/l and 1144 pmol/l those described later in this review as suffering from respectively) who developed profound hypoglycaemia metastatic cancer. immediately after excision of a pheochromocytoma. A somewhat similar distinction between two types of Plasma insulin levels were also abnormally high, relative hepatoma to that suggested by McFadzean & Yeung to their prevailing blood glucose levels, in the remaining (1969) was drawn by Wu et al. (1988) who noted that eight patients (Akiba et al. 1990). patients with hypoglycaemia tended to have higher plasma In two patients with fasting hypoglycaemia due to IGF-II and lower plasma IGF-I levels than those without pheochromocytoma studied by Gorden et al. (1981) it. plasma levels of ‘IGF-like materials’ were described as In the hypoglycaemic patients a larger proportion of modestly raised. It seems probable, therefore, that the IGF-II was in the form of partially processed or ‘big pheochromocytomas, like most other tumours, can IGF-II’, their plasma IGF-II:IGF-I ratios were higher and produce fasting hypoglycaemia by secreting ‘big’ IGF-II. GH levels lower than in normal subjects or hepatoma patients who did not become hypoglycaemic. Treatment Lymphomas, myeloma and leukaemia with GH reduced their glucose requirements but did not Hypoglycaemia occurs as an unusual phenomenon in completely relieve their hypoglycaemia. patients with various types of lymphoma (Wanebo et al.

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1966) usually as a terminal event. Very occasionally it is Myeloma and primary monoclonal gammopathy the presenting feature (Braund et al. 1987, Walters et al. An association between hypoglycaemia and myeloma was 1987). It is also a well-recognised complication of first reported 25 years ago and that with monoclonal leukaemia, especially in animals, but also in rare human gammopathy more recently (Russell-Jones et al. 1990, cases (Hilali et al. 1984, Makino et al. 1985). Sometimes Arnqvist et al. 1993). The cause of the hypoglycaemia is the hypoglycaemia in leukaemia is artefactual due to post- not, however, the same in all cases. collection disappearance of glucose from the blood In the case of myeloma reported by Snowden et al. through glycolysis (Astles et al. 1995). But more often it (1994) an increased proportion of the IGF-II present in the is real. Increased plasma lactate levels are sometimes plasma was of the ‘big’ variety and the IGF-II:IGF-I observed in patients with hypoglycaemia caused by ratio was abnormally high. Onset of spontaneous hypo- leukaemia (Makino et al. 1985) just as in patients with glycaemia was marked by reversal of the patient’s long- hypoglycaemia and lymphoma or fibrosarcoma (Laurent standing need for insulin to control her NIDDM which et al. 1971, Marks & Rose 1981, Durig et al. 1996). began 15 years earlier. Anti-insulin antibodies were not detected in her serum. Insulin-receptor antibodies In the cases of monoclonal gammopathy described by Wasada et al. (1989) and by Redmon et al. (1992) hypo- Evidence for the existence and pathogenic role of glycaemia appears to have been insulin mediated and due stimulatory insulin-receptor antibodies in hypoglycaemia to its delayed release from insulin-specific mono-clonal caused by Hodgkin’s disease has been produced by two autoantibodies in a manner resembling that seen in insulin groups of authors (Braund et al. 1987, Walters et al. 1987). autoimmune syndrome (IAS). This was true also for the IGF-II was not measured in either of the cases reported but case of myeloma described by Merlo et al. (1992) whose in one of them IGF-I, measured by bioassay, was said to monoclonal (pro)insulin binding immunoglobulin was be just below the reference range. Plasma GH measured produced by the neoplastic cells. during spontaneous hypoglycaemia was 12.5 U/l, which is higher than is customarily found in patients with IGF-II- In this form of NICTH, endogenous insulin - released secreting tumours and consistent with the view that some in response to ingestion of a meal but rendered temporarily mechanism other than excessive IGF-II production was ineffective by binding to the autoantibody - is slowly involved. released during the post-absorptive period producing an apparently inappropriate hyperinsulinaemia. But whereas Despite the passage of more than 10 years since these IAS is self-limiting, and part of a more general auto- two reports were published, no other cases of lymphoma- immune disorder, monoclonal gammopathy appears to be induced hypoglycaemia in which antibody receptors were a neoplastic disorder in which the para-protein produced implicated have, to our knowledge, been described. has a specific affinity for insulin or proinsulin. In this context it is of interest that in the seven or so patients with hypoglycaemia and lymphoma investigated Hypoglycaemia and metastatic cancer by Gorden et al. (1981) the concentration of plasma ‘IGF- Hypoglycaemia may occur as a terminal or agonal event like material’, measured by a radioreceptor binding assay in patients dying from metastatic disease (Younus et al. and equating largely with multiplication-stimulating 1977, Marks & Rose 1981). It is assumed to have a activity (now known to be identical with IGF-II) was different cause from hypoglycaemia occurring as a either low, or very low compared both with a normal dominant and comparatively ‘early’ feature (Marks et al. reference population and patients suffering from other 1965, MacDougall et al. 1986) in rare cancer patients types of tumour-producing NICTH. In a further case of (especially those with primary tumours of the lung, hypoglycaemia due to Hodgkin’s disease investigated by stomach, pancreas, caecum and colon) in whom plasma us, plasma insulin, C-peptide and proinsulin levels were insulin and GH levels are depressed and the IGF-II:IGF-I all suppressed, and IGF-I, IGF-II and IGF-II:IGF-I ratio ratio unusually high. were normal. Neither insulin autoantibodies nor insulin- Hypoglycaemia occurring in patients with over- receptor antibodies were measured. whelming metastatic disease was formerly attributed to The role of stimulatory, insulin-receptor antibodies in ‘liver failure’ secondary to its destruction by the tumour. the pathogenesis of NICTH by neoplasms other than An equally plausible explanation, as yet unconfirmed lymphomas has been established by various workers (Fitzpatrick et al. 1995), is that it is mediated by various (Rochet et al. 1989, Taylor et al. 1989). It is reasonable to cytokines including TNF-α, and interleukin-1 and -6 assume, therefore, that they are involved in at least some which are known to produce profound hypoglycaemia in of the rare cases of hypoglycaemia secondary to animals (Mahony & Tisdale 1990, Clark et al. 1992, lymphoma. Battelino et al. 1996) and probably also in human beings.

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They are currently thought to be involved in the impossible (Cohen et al. 1986, Hampton et al. 1988, production of hypoglycaemia in septicaemia and over- Nauck et al. 1990, Tasaka et al. 1993, Gorden et al. 1995). whelming infections with malaria parasites (Krishna et al. The ‘gold standard’ for the diagnosis of hyper- 1994, Rockett et al. 1994) possibly by stimulating insulin insulinism remains Whipple’s triad (which consists of release (Elased et al. 1996). The situation is, however, still symptoms due to hypoglycaemia demonstrated during far from clear. fasting and which are relieved exclusively by intravenous glucose) plus the presence of inappropriately high Diagnosis peripheral plasma IRI (>30 pmol/l), C-peptide (>300 pmol/l) and proinsulin (>20 pmol/l) levels in the The diagnosis of NICTH commences with its recognition presence of fasting (or exercise-induced) hypoglycaemia. as the cause of the patient’s neuroglycopenic symptoms. When these conditions are met the diagnosis of This rarely poses any problem providing the possibility insulinoma can be made preoperatively with as much is considered since fasting hypoglycaemia, once it has certainty as is realistically possible. If they are not, some developed, is relentless and easily confirmed by other explanation for the patient’s hypoglycaemia should measurement of the blood glucose concentration. It be sought. proceeds through differential diagnosis (Marks & Teale Although it is fashionable to do so, calculation of a 1996) to elucidation of the cause upon which rational and ‘glucose:insulin ratio’ does not determine the specific treatment depends. Only the differential diagnosis appropriateness of insulinaemia (C-peptidaemia) during of fasting hypoglycaemia will be considered here. hypoglycaemic episodes. The ratio is not only method- dependent but also scientifically spurious and should Insulinoma never be used (Hattori et al. 1994). Instead a reference Diagnosis depends upon establishing inappropriate insulin range for plasma insulin, proinsulin and C-peptide (or rarely proinsulin) secretion during hypoglycaemia concentrations in the presence of hypoglycaemia provoked by fasting or rigorous exercise. Paradoxically (<2.2 mmol/l in children and young adults; <3.0 mmol/l in the measurement of C-peptide in plasma is a more subjects over 60 years of age) should be established sensitive indicator of inappropriate secretion than the against which those obtained in patients with hypo- measurement of insulin itself (Hattori et al. 1994) as the glycaemia can be assessed (Marks & Teale 1996). concentration of C-peptide may be raised in peripheral C-peptide suppression tests, in which plasma blood even when that of insulin is suppressed. This C-peptide levels act as a surrogate for endogenous insulin anomaly, which has also been reported in children with production, have enjoyed considerable popularity ever PHHI (nesidioblastosis) is probably due to a greater than since the discovery of C-peptide and assays for measuring normal fractional extraction of insulin by the liver. This it became available. They are, however, no more than leaves the C-peptide unaffected and consequently free to screening tests capable of reducing to a manageable size appear in peripheral blood at an inappropriately high level. the number of patients in whom the rigorous exercise test Inappropriate C-peptidaemia (i.e. >100 pmol/l) and or admission to hospital for prolonged fasting are in order hyperinsulinaemia (i.e. >30 pmol/l) in the presence of since the incidence of both false positives and false fasting hypoglycaemia (blood glucose <2.2mmol/l) is negatives is high. Their main value is for distinguishing virtually pathognomonic for insulinoma or PHHI except recurrence of hyperinsulinism following successful when there is accidental or deliberate overdosing with removal of one insulinoma when others were also present sulphonylurea or other insulinotrophic drugs. Hyper but missed at operation from a recurrence of symptoms C-peptidaemia may also, very rarely, appear to occur in from psychogenic origin (Sata et al. 1995). those patients with IAS in whom the autoantibodies (to None of the many stimulation tests, e.g. tolbutamide, endogenous proinsulin) bind C-peptide as well as insulin glucagon, L-leucine, intravenous or oral glucose tolerance (Russell-Jones et al. 1990, Merlo et al. 1992). The high tests, that have been advocated over the past half-century titre of autoantibodies that are invariably present in AIS adds materially to the diagnosis (Marks & Rose 1981, makes distinction from insulinoma comparatively easy Marks 1989). Their use should be discontinued except providing the possibility is considered and excluded. where facilities for C-peptide, insulin and proinsulin Hyperproinsulinaemia (>20 pmol/l) is not diagnostic measurement are not available. of any single condition. Nevertheless the presence in plasma of proinsulin at a concentration >50 pmol/l in a Localisation patient with a history suggestive of spontaneous fasting Almost every localisation technique has been hypoglycaemia is presumptive evidence of an insulin- advocated as a preoperative aid to surgical removal of oma, whilst its absence, or presence at concentration insulinomas but none withstands critical survey (Table 3). <20 pmol/l, renders the diagnosis unlikely though not This includes somatostatin receptor scintigraphy (not

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia specifically shown in Table 3) the latest fashionable insulin, C-peptide and proinsulin levels, and low GH localising technique and which, though very good for levels. It is established by the presence of an abnormally localising gastrinomas (86% positive), is no better than high IGF-II:IGF-I molar ratio (>10:1; normal ratio circa any other for localising insulinomas preoperatively (Pitre 3:1). et al. 1996, Zimmer et al. 1996). An increased concentration of the E-domain of IGF-II It is quite clear that no preoperative localising is also typically found but is not, in our experience, as technique - including endoscopic ultrasonography, predictive as the IGF-II:IGF-I ratio in arriving at a undoubtedly the most sensitive currently available - is diagnosis (Table 2). Measurements of IGF-II alone should sufficiently reliable to make a diagnosis of insulinoma if not be relied upon for diagnosis and may be misleading. the biochemical findings are negative nor to justify delay Despite earlier optimism, measurements of IGFBPs in operating if they fail to localise a tumour proved have not proved clinically useful as yet but have helped to biochemically to be present (Daggett et al. 1981, Owens throw light on the mechanism by which tumours produce et al. 1995, Marks & Teale 1996). NICTH. We expect, however, that measurements of ‘free’ In contrast to preoperative localisation, intraoperative IGF-II and IGF-I will be so when they become more ultrasonography has proved to be extremely useful by readily available and have been properly evaluated enabling even experienced surgeons to localise tumours (Chung & Henry 1996, Moller et al. 1996). that their unaided fingers have missed. Localisation of the IGF-II-secreting tumour producing NICTH rarely gives rise to difficulty once the diagnosis NICTH has been established. Occasionally, however, when the The diagnosis of NICTH is suggested by the association tumour is unusually small or obscured by the pelvis, for of severe fasting hypoglycaemia with low plasma NEFA example, it may come to light only after very thorough and β-hydroxybutyrate levels and undetectable plasma investigation using modern imaging techniques. Since

Table 3 Accuracy of localisation of insulinomas for various imaging techniques: literature survey.

Number positive

Preoperative Intraoperative Endoscopic Authors Angiography CAT MRI Catheter ultrasound ultrasound ultrasonograph

Katz et al. (1986) 6/15 1/5 11/13 1/6 Galiber et al. (1988) 14/26 7/23 17/28 21/28 Bottger et al. (1990) 20/30 3/14 10/13 12/16 Mårtensson et al. (1990) 6/15 2/5 11/11 1/6 Doherty et al. (1991) 9/26 4/23 2/8 17/22 6/23 Vinik et al. (1991) 13/32 4/25 0/4 29/29 Lightdale et al. (1991) 0/4 0/5 4/4 Liessi et al. (1992) 2/7 6/7 5/7 6/7 6/7 Pasieka et al. (1992) 18/41 9/35 34/36 Rosch et al. (1992) 32/39* Thompson et al. (1993) 8/15 2/13 0/1 6/13 9/11 Menegaux et al. (1993) 2/2 Thompson et al. (1994) 7/10 Chang et al. (1994) 5/10 3/8 4/4 1/8 1/1 1/1 Knobel et al. (1995) 0/1 0/1 1/1 0/1 1/1 Moore et al. (1995) 1/3 0/3 3/4 0/3 4/4 Pitre et al. (1996) 18/18 10/11 Schumacher et al. (1996) 8/14 Zimmer et al. (1996) 3/14 1/14 1/14 13/14

Total number positive 97/224 43/181 11/39 117/129 38/101 71/85 65/82

Percent positive 46 24 28 91 38 84 79

*Multicentre trial in endocrine pancreatic tumours: cases include, but not exclusively, insulinomas. CAT = computerised axial tomography; MRI = magnetic resonance imaging.

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Endocrine-Related Cancer (1998) 5 111-129 some of these tumours contain somatostatin receptors adriamycin are the most valuable is sometimes beneficial. which can be visualised using 111In-octreotide imaging Favourable results have also been achieved with hepatic (Perros et al. 1996) the possibility of using this technique artery thromboembolisation, which may produce re- to localise a hidden tumour or see whether it has missions lasting a year or more, and cryogenic destruction metastasised should be borne in mind in case of difficulty. of metastases. These manoeuvres can be repeated if and when relapse occurs (Krentz et al. 1996). Treatment NICTH Insulinoma Treatment of tumour-induced hypoglycaemia, as in all Patients with NICTH may undergo complete remission types of hypoglycaemia, can be divided into two phases; following surgical removal of a benign or locally palliation of an acute episode with intravenous glucose or invasive tumour. Even partial removal often reduces or intramuscular glucagon and definitive, specific treatment abolishes hypoglycaemia although it usually recurs if and directed at its ultimate cause. Intramuscular glucagon will when the tumour re-establishes itself. invariably relieve fasting hypoglycaemia in patients with Complete removal of the tumour abolishes any insulinoma, but, because of its propensity to stimulate tendency to fasting hypoglycaemia. It also produces a rise endogenous insulin secretion, may cause profound in IGF-I and restores the blood glucose and plasma insulin rebound hypoglycaemia unless food is given as soon as the responses to food to normal. Immunoreactive IGF-II swallowing reflex is re-established. levels fall - even if they were not abnormally high (in Benign insulin-secreting tumours are best treated absolute terms) preoperatively - and the IGF-II:IGF-I ratio surgically unless there are overwhelming clinical reasons returns to normal (i.e. <10). The plasma GH and glucagon for not doing so. Removal of an adenoma is extremely responses to hypoglycaemia and other appropriate stimuli effective although some long-term follow-up series, but are restored and the plasma IGFBP-3 concentration rises not all, suggest that there may be an increased incidence to a level which, in molar terms, exceeds the combined of neuropsychiatric aberration, peptic ulcer disease and concentration of IGF-I and IGF-II (Perros et al. 1996, NIDDM in those who survived the operation (Dunn 1971, Teale & Marks 1998). Galbut & Markowitz 1980). Operative mortality is now Contrary to expectations, diazoxide-chlorothiazide down to less than 2% in the hands of experienced treatment often alleviates NICTH - though less pancreatic surgeons and virtually confined to those over predictably than with insulinomas. Both hGH and 70 years of age. In them palliative therapy with prednisolone have been used sometimes with great and diazoxide/chlorothiazide may be worth using since it is seemingly specific effect (Mitchell et al. 1965, Khaleeli et often remarkably effective and produces few if any al. 1991, Teale et al. 1992, Hunter et al. 1994, Agus et al. unpleasant side-effects. 1995, Katz et al. 1996, Perros et al. 1996). In the case of Malignant insulin-secreting tumours are often very hGH the effect was thought to be mediated by increasing slow growing and providing hypoglycaemia can be the production of IGFBP-3 but this now seems unlikely avoided many years of good life may follow initiation of (Teale & Marks 1998). In the past the failure to observe a antihypoglycaemic therapy and/or ablation of the primary sustained beneficial effect of exogenous hGH after an tumour and as many of the metastases as possible (Marks early favourable response was reported and may have & Rose 1981, Krentz et al. 1996). been due to the relatively low doses used or to the Palliative drug therapy with a combination of development of GH-specific antibodies (Samaan et al. diazoxide and a diuretic thiazide is often effective in 1990). relieving the hypoglycaemia if this persists after surgery. Long-acting and synthetic somatostatin preparations have Large doses of prednisolone may bring about a been used with varying success in palliation. They may remarkable improvement in both glucose homeostasis and either improve hypoglycaemia, by inhibiting insulin other biochemical markers of NICTH (Baxter et al. 1995, secretion by the tumour, or worsen it by inhibiting Perros et al. 1996). In particular there is a rise in plasma secretion of the counterregulatory hormones - glucagon ALS and IGFBP-3 levels (Teale & Marks 1998) and a fall and somatotropin - without affecting insulin production in ‘big IGF-II’ (Baxter et al. 1995). The insulinaemic itself (Alberts & Falkson 1988, Stehouwer et al. 1989, response to oral glucose is restored and there may be Gama et al. 1995, Meeking et al. 1997). Since improve- restoration of the endogenous GH response to appropriate ment is commoner than the reverse a therapeutic trial is stimuli including hypoglycaemia. probably worthwhile. Treatment with other anti-inflammatory and immuno- Tumoricidal therapy with streptozotocin and other suppressive agents is worthy of trial in cases where insulin antineoplastic agents of which 5-fluorouracil and antibodies are implicated. It may produce prolonged

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Downloaded from Bioscientifica.com at 09/27/2021 04:07:17AM via free access Marks and Teale: Tumours producing hypoglycaemia remissions (Taylor et al. 1989) as may specific antitumour Baxter RC, Holman SR, Corbould A, Stranks S, Ho PJ & Braund chemotherapy. W 1995 Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia. Journal of Clinical References Endocrinology and Metabolism 80 2700-2708. Agus MSD, Levit Katz LE, Satin-Smith M, Meadows AT, Hintz Berger M, Bordi C, Cuppers H-J, Berchthold P & Gries FA 1983 RL & Cohen P 1995 Non-islet-cell tumor associated with Functional and morphologic characterization of human hypoglycemia in a child: successful long-term therapy with insulinomas. Diabetes 32 921-931. growth hormone. Journal of Pediatrics 127 403-407. Bottger TC, Weber W, Beyer J & Junginger T 1990 Value of Akiba M, Kodama T, Ito Y, Obara T & Fujimoto Y 1990 tumor localization in patients with insulinoma. World Journal Hypoglycemia induced by excessive rebound secretion of of Surgery 14 107-112. insulin after removal of pheochromocytoma. World Journal of Braund WJ, Naylor BA, Williamson DH, Bailey ID, Clark A, Surgery 14 316-324. Chapel HM & Turner RC 1987 Autoimmunity to insulin Alberts AS & Falkson G 1988 Rapid reversal of life-threatening receptor and hypoglycaemia in patients with Hodgkin’s hypoglycaemia with a somatostatin analogue (octreotide): a disease. Lancet i 237-240. case report. Journal of South African Medicine 74 75-76. Bruno MS & Ober WB 1962 Hypoglycemia and intrathoracic Alsever RN, Roberts JP, Gerber JG, Mako ME & Rubenstein AH mass. New York State Journal of Medicine 62 2005-2008. 1975 Insulinoma with low circulating insulin levels: the Bugalho MJ, Roque L, Sobrinho LG, Hoog A, Nunes JF, diagnostic value of proinsulin measurements. Annals of Almeida JM, Leitao CN & Santos JR 1994 Calcitonin- Internal Medicine 82 347-350. producing insulinoma: clinical, immunocytochemical and Arnqvist HJ, Halban PA, Mathiesen UL, Zahnd G & von Schenck cytogenetical study. Clinical Endocrinology 41 257-260. H 1993 Hypoglycaemia caused by atypical insulin antibodies Chang HY, Huang HS, Lin JD, Huang BY, Huang MJ & Jeng LB in a patient with benign monoclonal gammopathy. Journal of 1994 Insulinoma - clinical experience in ten cases. Chang Internal Medicine 234 421-427. Keng I Hsueh 17 28-38. Astles JR, Petros WP, Peters WP & Sedor FA 1995 Artifactual Chiang WL, Tsai MH, Lieu CS, Yang SF & Lin PC 1993 hypoglycemia associated with hematopoietic cytokines. 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