Da-ming Zhang,and Nai-shi Li

Department of Endocrinology,Key Laboratory of Endocrinology,Ministry of Health,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

INSULINOMA is the most common cause of hypoglycemia.Although it is a rare disease,there has been a significant progress in its diagnosis along with the technology development.A set of diagnostic criteria for insulinoma has been internationally recognized,consisting of qualitative diagnosis and level diagnosis,the former one of which means the patients have to demonstrate hypoglycemia and hyperinsulinemia at the same time.1For determination of the location of insulinoma,several new methods have been developed including ultrasonic endoscope,somatostatin receptor scintigraphy,and pancreas perfusion CT.2-4The first choice for insulinoma treatment is surgery,most of which could be performed with minimal invasion nowadays.While 70 years ago,it was impossible to test blood insulin level precisely since radioimmunoassay was not invented until 1950s;and back in those days the available radio imaging technology was no more advanced than X ray,which could make little contribution to locate insulinoma.Under that circumstance,Professor Liu Shih-hao and his colleagues still managed to diagnose the first insulinoma documented in China,which was excised in surgery by Harold H.Loucks,at that time chief of surgery department in Peking Union Medical College (PUMC).Besides the diagnosis and treatment,Professor Liu Shih-hao and his colleagues did elaborate researches on the conditions of this case.The paper based on those studies was published inThe Journal of Clinical Investigationin 1936.5The careful clinical observations,meticulous analysis,and thorough medical consideration in his work left us a rich legacy.

BEFORE LIU’S WORK

Pancreatic islets were first discovered by Langerhans in 1869,who was a medical student at that time.6Then insulinoma was described in some pathological studies.7,8After the discovery of insulin by Banting and Best in 1922,9scientists have found more information about the functions of insulinoma.In 1922,Fletcher and Campbell first identified insulin excess as an etiology of hypoglycemia.10Shortly after that,Harris observed a group of hypoglycemia patients who demonstrated symptoms of insulin excess without receiving insulin treatment and the symptoms mitigated after food intake.Upon those findings,he proposed the hypothesis of“spontaneous hyperinsulinemia”.11A similar case was noticed by Liu Shih-hao and Chang Hsiao-chien in PUMC Hospital in 1925.12The first verification of Harris’ hypothesis appeared in a report by Wilder et al13in 1927,who performed the first insulinoma surgery in the world.However,the prognosis was not improved in their case because the patient had already developed hepatic metastasis.Two years later,Howland et al14reported a case of pancreatic islet adenoma diagnosed before operation,confirmed in surgery,and excised with favorable result.Four years later,Liu Shih-hao,Harold H.Loucks,Chou Shou-kai,and Chen Kuo-chen reported a male case of insulinoma diagnosed and treated in PUMC Hospital.

DESCRIPTION OF THE CASE

The paper published in 1936 by Liu Shih-hao et al is remarkable not only because it is the first case report about this disease in China,but also because the detailed research recounted in that 12-page article illuminates how to diagnose insulinoma,providing guidance for clinical practice.Apart from the immediate implications,the study on that patient’s diagnosis and treatment reflects the concept of“from bench to bedside”,which is the rudiments of translational medicine.

The meticulous description of symptoms and signs in that case report is still exemplary even in these days.A comprehensive picture is drawn about the conditions of the patient,starting from general information including ethnicity,gender,age,occupation,and admission date.The hypoglycemia symptoms described in the patient’s history includes:time of onset;situations that ever induced the attack;symptoms when hypoglycemia attacked,especially those involving central nervous system such as clouded consciousness,twitching movements of limbs,and convulsions;attack frequency,which increased over time;the feature that symptoms were relieved after food intake;abnormally growing weight and increasing appetite.5It is worth mentioning that doctor Chu Hsien-i,who saw this patient first in the Outpatient Clinic of the Hospital,suggested the diagnosis of hypoglycemia syndrome.From this elaborate report we can learn clearly the clinical features of that patient.Although Whipple and Frantz have published a series of reports on insulinoma cases and proposed“Whipple triad”,15the clinical symptoms of insulinoma in hypoglycemia attack were various.The full-scale description of hypoglycemia in Liu et al’s article provided a helpful tool for doctors in 1930s at which time the laboratory techniques were not as developed as they are today.

After physical examination and laboratory tests,the diagnosis of hypoglycemia was confirmed.The patient observed a series of symptomatic treatment,then received a laparotomy under ether anesthesia on January 2,1935.During the operation,a tumor of 2.5 cm in diameter was found lay along the upper margin of the right half of the body of the pancreas,at approximately where the head joints the body.The tumor was eradicated,another such case after the 17 successful surgeries counted in the review of Whipple and Frantz.15After comparing preoperative and postoperative change of blood glucose,the authors were sure that the patient’s hypoglycemia had been cured and confirmed this conclusion in further follow-up.

CLINICAL RESEARCH

When the patient was in hospital,Liu Shih-hao did a series of observations on his symptoms,blood glucose level,and treatments.Through observing the postabsorptive blood glucose change,Liu Shih-hao discovered that the values,although low to start with,were below normal even at maximum level after meals.The more significant abnormality lies in the failure of the blood sugar to maintain at a normal level during the postabsorptive period.Within 4 to 5 hours after each meal when absorption could hardly be complete,the blood glucose promptly fell to the subnormal level.

It was suggested in their report that the hypoglycemic syndrome in this patient can be divided conveniently into three stages.The first stage was characterized by drowsiness and a gradually deepening depression.The second stage was ushered in by excitement,which progressed into the convulsive seizures of the third stage.During the first stage,which lasted for an hour,there was no significant decrease of blood sugar compared with that in the period of relative well-being.Even when the second stage was reached,the lowering of blood sugar was slight,if any.It was not until after the convulsions had started that definite further lowering of the blood sugar occurred.It was inferred from these observations that hypoglycemia had to be maintained for a certain length of time,which in this patient amounted to over two hours,before the central nervous system suffers sufficiently to manifest the damage in the form of convulsions.It seems that,according to Liu et al,besides the level of the hypoglycemia,the duration is another important determining factor in the manifestations of symptoms.At that time,blood glucose level could not be tested quickly,so this conclusion was valuable for treating hypoglycemia.In stages 1 and 2,symptomatic treatment was the first choice to avoid progressing into stage 3.As related in that article,they gave the patient 3 500-calory diet containing 600 grams carbohydrates to prevent the attack of hypoglycemia.

Liu closely observed the efficiency of all kinds of symptomatic treatments for hypoglycemia proposed internationally at that time.The first type was medication,such as adrenine,hypophysin,and ephedrine,which were found not effective in that patient.The second was glucose per rectum and by mouth,the latter one of which,after comparison,was found more efficient.In addition,he found out that fructose was not a good choice for hypoglycemia patients.Those attempts contribute to establishing effective and appropriate symptomatic treatments for hypoglycemia.

TRANSLATIONAL RESEARCH

One of the bright spots of the work by Liu et al is the biological assay of insulin,adopting the extraction method used by Best,Jephcott,and Scott on cow pancreas.16A portion of the tumor (1.92 gram) was extracted,producing up to 20 mL extract.The assay was done on two rabbits of comparable weight which had been deprived of food for 24 hours prior to injection of tumor extract.The extent and duration of hypoglycemia in both rabbits after the injection approximated those induced by 0.5 unit of insulin.Based on that finding,it was speculated that the tumor tissue contained about 10 units of insulin per gram,much higher than the concentration in beef pancreas (3 units per gram).15The high insulin content of the tumor justifies the diagnosis of hyperinsulinism in this patient.The semidetermination test on insulin helped they in identifying the tumor function and reaching a dinical diagnosis.It is a typical model of translational medicine synchronizing with clinical practice,which is still much advocated today.

Liu et al conducted tests with 170 grams of glucose before and after operation,carefully recorded and calculated blood glucose,metabolic rate,and respiratory quotient before and 4 hours after glucose ingestion.In those physiological tests,they found that the metabolic rate before and after glucose ingestion was greater than that after operation.The respiratory quotient lowered remarkably after operation,indicating the profound changes in the composition of the metabolic mixture brought about by the removal of the pancreatic adenoma.The obesity of this patient before surgical treatment was thought to be probably the result of predominant utilization of carbohydrate caused by insulin excess,together with overeating.From the perspective of preclinical medicine,their research was an attempt to illuminate the physiology of obesity;from the view of clinical medicine,when the detection of insulin is impossible due to technique limitation,the physiological tests could indirectly reflect hyperinsulinemia.That research was also an attempt to find clinical indicators of hyperinsulinemia,which was meaningful for identification of hypoglycemia at that time.This part of their work was also a good example of translational medicine,applying findings of preclinical research to clinical diagnosis.

WHAT BACKED LIU’S WORK

The substantial of the article by Liu and his colleagues has not faded over time,as it is the fruit born from well prepared soil,a building resting on three pillars:the first-class facilities of PUMC then,the talented researchers in that group,and the development in that field in 1930s.

When reading Liu’s case report with other similar articles by western researchers at the same period,we notice the comparability in equipment and instruments.The laboratory animals were readily available and there were metabolic wards in PUMC Hospital,really as good as contemporary western hospitals.The library of PUMC was of similar value in backing their research.The report was published in December 1935,in which the review of Whipple and Frantz appeared in the same year was enlisted in the references,reflecting how timely the College was in obtaining and providing the latest publications.

As a medical college funded by Rockefeller financial group,which supported the modern medical education mode proposed by John Hopkins,PUMC embraced the new concept in medical education and training.The authors of that case report,except for doctor Loucks,were all graduates of PUMC and members of endocrinology research group in the Department of Medicine.The students in PUMC received advanced medical training at that time,some of whom would be eliminated for their low-ranking grades,ensuring that the survivors would be competent and talented doctors and researchers.

The third prerequisite is the opportunity provided by the discovery of insulin.Before insulin was discovered,it was impossible to understand insulinoma;after the application of insulin in clinical practice in 1922,its side effect was summarized and compared with the symptoms encountered in insulinoma patients.Liu co-authored a case report of hypoglycemia with Chang Hsiao-chien in 1925,showing his interest in glucose metabolism at that time.In 1927,he did research on the influence of insulin on blood glucose,cholesterol,and glycerol in renal disease patients.In a word,the developed understanding of insulin helped prepare those researchers in knowledge for performing the work they fulfilled and materialized in that case report on insulinoma.

The detailed research,full-scale description,careful experiment design,and advanced translational medical thought,all reflect the clinical and scientific style of the group led by Professor Liu Shih-hao.More than 70 years have passed,and we are still inspired and awestruck while reading his paper again.In the 110thanniversary of the birth of Professor Liu,we present this article in memoriam of him.

ACKNOWLEDGEMENT

We express our thanks here to Min Wang and Yan-wu Zhang in Institute of Medical Information,Chinese Academy of Medical Sciences &Peking Union MedicalCollge for helping with literature search.

1.Cryer PE,Axelrod L,Grossman AB,et al.Evaluation and management of adult hypoglycemic disorders:an endocrine society clinical practice guideline.J Clin Endocrinol Metab 2009;94:709-28.

2.Xue HD,Jin ZY,Liu W,et al.Perfusion characteristics of normal pancreas and insulinoma on multi-slice spiral CT.Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2006;26:68-70.

3.Zhao YP,Cong L,Zhang TP,et al.Diagnosis and treatment of 404 cases of insulinoma.Chin J Pract Surg 2008;28:357-9.

4.Yue X,Gu F,Xia WB,et al.Qualitative diagnosis and localization of insulinoma before surgery-review of 99 cases.Chin J Pract Intern Med 2006;26:1795-7.

5.Liu SH,Loucks HH,Chou SK,et al.Adenoma of pancreatic islet cells with hypoglycemia and hyperinsulinism:report of a case with studies on blood sugar and metabolism before and after operative removal of tumor.J Clin Invest 1936;15:249-60.

6.Jolles S.Paul Langerhans.J Clin Pathol 2002;55:243.

7.Neve ET.The morbid anatomy of the pancreas.Lancet 1891;138:659-61.

8.Nicholls AG.Simple adenoma of the pancreas arising from an island of langerhans.J Med Res 1902;8:385-95.

9.Banting FG,Best CH.The internal secretion of the pancreas.J Lab Clin Med 1922;7:251-66.

10.Fletcher AA,Campbell WR.The blood sugar following insulin administration and the symptom complex-hypoglycemia.J Met Res 1922;2:637-49.

11.Harris S.Hyperinsulinism and dysinsulinism.JAMA 1924;83:729-31.

12.Liu SH,Chang HC.Hypoglycemia,report of a case unassociated with insulin administration.Arch Intern Med 1925;36:146-8.

13.Wilder RM,Allan FN,Power MH,et al.Carcinoma of the islands of the pancreas.Hyperinsulinism and hypoglycemia.JAMA 1927;89:348-55.

14.Howland G,Campbell WR,Maltby EJ.Dysinsulinism:convulsions and coma due to islet cell tumour of pancreas with operation and cure.JAMA 1929;93:674-9.

15.Whipple AO,Frantz VK.Adenoma of islet cells with hyperinsulinism.A review.Ann Surg 1935;101:1299-355.

16.Best CH,Jephcott CM,Scott DA.Insulin in tissues other than the pancreas.Am J Physiol 1932;100:285-94.