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Intermittent jaundice and rigors in a than other patients with pancolitis. The patient with longstanding ulcerative clearest evidence for this is a large case-control colitis study comparing this subgroup with matched controls with ulcerative colitis but no PSC. Q1: What does the PTC (fig 1; see p 406) This suggested a threefold risk of developing show and given the history of ulcerative colorectal cancer or dysplasia over and above colitis what is the most likely diagnosis? the control group.3 Previous studies had The PTC shows strictures, dilatation, and provided conflicting evidence due to small irregularity of the intrahepatic ducts, with little sample size, referral bias, failure to adequately or no flow of contrast into the common hepatic match cases and controls in terms of disease duct. The features are suggestive of primary duration, and extent or their maintenance sclerosing cholangitis (PSC) in this patient treatment leading to overestimation of the risk. with long standing ulcerative colitis. With PSC as a risk factor for the development of apparent obstruction at the porta hepatis, the colonic cancer or dysplasia in patients with diVerential diagnosis must include a cholangio- ulcerative colitis is therefore probably inde- carcinoma complicating PSC. pendent of the risk conferred by longstanding Estimates of the prevalence suggest PSC to total colitis. This question of additional risk to be present in 2.4–7.5% of patients with ulcera- ulcerative colitis patients with PSC is of some tive colitis and approximately two thirds of importance when considering colonic surveil- patients with PSC have an underlying inflam- lance, especially as patients with ulcerative matory bowel disease confirming a strong colitis and PSC may have had subclinical coli- association between the two conditions. PSC is tis for several years before developing colitic commoner in young males, but aVects all age symptoms. With a cumulative risk of colorectal groups. Several HLA haplotypes, including cancer at 10 years of up to 25% in this group, HLA-B8, HLA-DR2, HLA-DR3 and HLA- annual colonoscopic screening has been rec- Dw52A, have been linked with the condition ommended. The patient had low grade dyspla- and its association with other autoimmune sia within a raised lesion in the context of conditions suggests immunological attack plays ulcerative colitis. This has been termed a an important part in the pathogenesis. It may dysplasic associated lesion or mass (DALM). predate colitic symptoms or, as in this case, be Evidence suggests that upto 40% of such cases seen to complicate established colitis. Symp- will already have a cancer within the colon and toms of colitis in patients with PSC are often that they should undergo colectomy.4 few or absent, the disease seems to run a milder http://pmj.bmj.com/ course than in patients with ulcerative colitis Q3: Given the deteriorating liver function without PSC or even be subclinical. In one tests, computed tomography findings, series, seven out of nine patients diagnosed and colonoscopic changes how would you with PSC but with no obvious symptoms of manage this case? colitis who went on to have colonoscopy had The progressive, non-fluctuating rise in bi- histological evidence of colitis.1 Both intrahe- lirubin level, in the absence of sepsis, coupled

patic and extrahepatic ducts can be involved in with the signs of decompensated liver cirrhosis on September 25, 2021 by guest. Protected copyright. the inflammation and fibrosis which character- suggest progression to end stage liver failure. ises PSC. This leads to strictures and localised Optimal timing for transplant in PSC patients dilatation within these ducts. There is a has not been clearly defined and early referral is 15%–20% cumulative life risk of developing a recommended. Referral should be made if cholangiocarcinoma and the risk of developing there is a non-fluctuating increase in serum carcinoma of the gallbladder is also increased. bilirubin (>100 µmol/l), significant impairment Choledocholithiasis may complicate PSC. Pa- of synthetic liver function ensues, of if life tients presenting with calculi share the same threatening complications of decompensated epidemiological features, extent of radiological cirrhosis develop (for example, spontaneous changes, HLA typing and risk of malignancy as bacterial peritonitis, variceal bleeding, en- PSC patients not presenting with calculi.2 Most cephalopathy).5 Prognostic models have been patients with calculi are symptomatic at developed in an attempt to guide clinicians as presentation and recurrent episodes of ascend- to timing of referral to the transplant centre. ing cholangitis are not uncommon. This is the These are based on clinical and biochemical likely cause of the initial presenting symptoms parameters correlating with prognosis on mul- and operative findings in this case. tivariate analysis of retrospective clinical series of PSC patients. However, clinical models Q2: What is the connection between this which apply to populations have wide confi- hepatological diagnosis and the findings dence intervals when applied to individuals of dysplasia at colonoscopy? and care needs to be taken not to become over- The subset of patients with ulcerative colitis reliant on such scoring systems.5 None of these and PSC seem to be at even greater risk of clinical or laboratory parameters predict the developing colorectal dysplasia and cancer development of cholangiocarcinoma, the most

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serious complication of PSC, which may Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from preclude curative treatment by orthotopic liver Box 1: Potential causes of NICTH transplant (OLT). Further investigation of the Tumours of mesodermal origin cystic mass lesion in this patient showed no x Fibroblastomas. evidence of cholangiocarcinoma. x Fibromas. In this patient, the presence of low grade x Fibrosarcomas. colonic dysplasia within a raised lesion x Haemangioendotheliomas. (DALM) is worrying and suggests he requires x Histiocytomas. colectomy due to the high risk that cancer has x Leiomyosarcomas. already developed in his colon. Furthermore, x Mesenchymal tumours of the diaphragm, the risk of developing a subsequent colonic pancreas, and pleura. cancer has been shown to be increased further x Mesoblastic nephromas. in those patients with PSC and ulcerative coli- x Mesotheliomas. tis who retain their colon after OLT and who Tumours of epithelial origin then require long term immunosuppression. x Adrenal carcinomas. Given the combination of end stage liver x Carcinomas of the gastrointestinal tract, failure secondary to PSC and the need for sur- lung, or prostate. gical management of the colonic dysplasia the x Hepatomas. patient was transferred to Queen Elizabeth x Medullary thyroid carcinoma. Hospital, Birmingham. Three management Tumours of haemopoietic origin strategies were possible: (1) colectomy follow- x Leukaemia (chronic myelocytic leukae- ing OLT at a later date, (2) OLT followed by mia). colectomy at a later date, or (3) a combined x Lymphoma. procedure. Colectomy followed by OLT in the context of such deteriorating liver function Tumours of neuroectodermal origin would not be an option as it would carry a very x Neuroblastoma. high mortality rate. OLT with colectomy at a later date is not ideal as there is a high risk of therapy are not supported by history. Liver colonic cancer already having developed failure, an insulinoma, and adrenal failure are which, in theory at least, may be potentiated by refuted by investigation results. Undetectable post-OLT immunosuppression. Despite the insulin and C peptide concentrations during potential additional morbidity and risk of post- hypoglycaemia, with normal liver and adrenal operative infection carried by the combined function tests, suggest the diagnosis of procedure this was the preferred option. The NICTH. possibility of discovery of a cholangiocarci- noma at operation which would preclude OLT Q2: What pharmacological agents may was explained to the patient. The combined alleviate his hypoglycaemia? procedure was successful and he made a full Recombinant human growth hormone in- recovery. There was no evidence of tumour in creases IGF-I and IGFBP-3 concentrations, http://pmj.bmj.com/ either liver or colonic resection specimens. He and therefore reduces the bioavailability of remains well on standard immunosuppression “big” IGF-II. Prednisolone helps by increased four years later. binding of “big” IGF-II to the acid labile sub- unit, and there is reduced secretion of “big” Final diagnosis IGF-II, thus leading to diminished bioavail- Decompensating cirrhosis and colonic dyspla- ability of IGF-II.1 Both these therapies are syn- sia complicating primary sclerosing cholangitis ergistic in controlling hypoglycaemia.

and ulcerative colitis. on September 25, 2021 by guest. Protected copyright. Q3: What is the role of surgery in 1 Broome U, Lofberg R, Lundqvist K, et al. Sub-clinical time management of this patient? span of inflammatory bowel disease in patients with primary Debulking or partial removal helps sympto- sclerosing cholangitis. Dis Colon Rectum 1995;38:1301–5. 2 Pokorny RS, McCaughan GW, Gallagher ND, et al. Sclero- matically in patients of mesothelioma present- sing cholangitis and biliary tract calculi—primary or ing with hypoglycaemia. This situation obtains secondary? Gut 1992;33:1376–80. 3 Shetty K, Rybicki L, Brzezinski A, et al. The risk of cancer or in most of the malignant or locally infiltrating dysplasia in ulcerative colitis patients with primary scleros- tumours. Complete alleviation of hypoglycae- ing cholangitis. Am J Gastroenterol 1999;94:1643–9. 4 Bernstein CN, Shanahan F, Weinstein WM. Are we telling mic symptoms is possible in cases where the patients the truth about surveillance colonoscopy in ulcera- tumour can be completely excised. tive colitis ? Lancet 1994;343:71–4. 5 Devlin J, O’Grady J. Indications for referral and assessment in adult liver transplantation—a clinical guideline. Gut 1999;45(suppl VI):VI 7. Box 2: Learning points Key diagnostic points for NICTH x Reduced ratio of IGF-I: IGF-II. An elderly man with pleural eVusion and x Raised “big” IGF-II. abnormal behaviour Treatment options in NICTH x Recombinant human growth hormone Q1: What is the cause of this patient’s can ameliorate symptoms. hypoglycaemia? x Steroids help symptomatically by dimin- The cause of the hypoglycaemia is non-islet cell ishing bioavailability of IGF-II. tumour hypoglycaemia (NICTH). IGF con- x Debulking or complete removal of centrations confirm this diagnosis. Other com- tumour leads to symptom remission. mon causes like insulin or sulphonylurea

www.postgradmedj.com 414 Self assessment answers Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from Discussion 3 Daughaday WH, Emanuele MA, Brooks MH, et al. Synthe- sis and secretion of insulin-like growth factor II by a leiomy- Patients with large mesotheliomas (particularly osarcoma with associated hypoglycemia. N Engl J Med sarcomatoid) weighing 1–10 kg may develop 1988;319:1434–40. 2 4 LeRoith D. Insulin-like growth factors (r a). N Engl J Med hypoglycaemia, particularly with fasting. 1997;336:633–40. Headache, fatigue, confusion, or seizures may 5 Zapf J. Role of insulin-like growth factor (IGF) II and IGF binding proteins in extrapancreatic tumour hypoglycemia. J occur. Patients with a large mesothelioma and Intern Med 1993;234:543–52. hypoglycaemia are likely to have NICTH. 6 Service FJ. Hypoglycemic disorders (r a). N Engl J Med Some of these mesenchymal (non-islet cell) 1995;332:1144–52. tumours produce and release “big” IGF-II,3 a prohormone form of IGF-II, which binds to insulin receptors as well as to IGF-I and IGF-II AdiYcult case of gastrointestinal receptors, and leads to hypoglycaemia. “Big” haemorrhage IGF-II directly stimulates the uptake of glucose by the tumour and by insulin responsive tissues Q1: Following the insertion of the like fat and muscle. Hepatic glucose produc- Sengstaken tube what additional tion and insulin secretion are decreased by management would you have instigated? hypoglycaemia and by the direct inhibitory The Sengstaken tube remains an eVective eVects of big IGF-II on the pancreatic â cells.4 measure for stopping variceal haemorrhage “Big” IGF-II inhibits the secretion of pituitary that can not be controlled by other means. growth hormone, which in turn decreases the However, its use requires expertise and careful synthesis and secretion of the ternary complex aftercare as a number of complications may of IGF-I, IGFBP-3, and the acid labile occur. Initially, only the gastric balloon should subunit.4 Diminished concentrations of be inflated, using 300 ml of air or water. If IGFBP-3 augment the eVects of circulating water is used to inflate the balloon, it is useful IGF-II. Big IGF-II interacts poorly with the to add a small amount of radiographic contrast IGFBP complex, and the resulting increase in medium, as this makes radiological checking of unbound IGF-II causes hypoglycaemia by the position of the tube easier. Once the inhibiting hepatic glucose production and balloon is inflated then it should be placed enhancing the disposal of glucose into muscle.4 under traction. Traditionally traction has been Surgical removal of the tumour or radiotherapy achieved by suspending a weight to the tube, reduces the excess IGF-II, thereby ameliorat- but this can be uncomfortable and may reduce ing the hypoglycaemia.4 patient tolerance of the tube. An alternative Once adrenal and hepatic diseases have been method of providing traction, that may be bet- excluded in a patient with significant hypogly- ter tolerated, is to tape the tube to the patient’s caemia, insulin and C peptide concentrations forehead under tension. Once the tube is should be measured. High insulin with sup- secured then its position should be confirmed pressed concentrations of C peptide raises the with a chest radiograph. Misplacement can possibility of exogenous insulin administra- lead to severe complications, such as oesopha- tion.5 Insulinoma, sulphonylureas, and sul- geal perforation. In most cases the inflation of http://pmj.bmj.com/ phonamides (in the presence of renal disease) the gastric balloon will result in cessation of lead to high insulin and C peptide concentra- haemorrhage. However, if there is continued tions.6 If insulin concentrations are low (hy- oesophageal bleeding, which is suggested by poinsulinaemic hypoglycaemia), like our pa- the continued ability to aspirate blood from the tient, then what is reducing the glucose? IGFs oesophageal aspiration port, then the oesopha- can do this and checking IGF-I, IGF-II, and geal balloon should be carefully inflated to 30 IGFBP-3 will help to clinch the issue. Another mm Hg using a manometer to check the pres-

possibility is due to insulin receptor antibodies, sure. Patients treated with a Sengstaken tube on September 25, 2021 by guest. Protected copyright. where growth hormone is raised, IGF-I and are at risk of developing aspiration pneumonia IGF-II are normal (unlike our patient), and and should ideally be managed in an intensive insulin receptor antibodies are present. care unit, where the airway can be protected if necessary by elective intubation.1 Prolonged Follow up use can lead to mucosal ulceration and an This patient was treated with recombinant attempt should be made to remove the tube human growth hormone subcutaneously and after 24 hours. Treatment with a vasoactive oral prednisolone. Tumour debulking was done drug should also be initiated and this is best by right pleurectomy. He is on postoperative done as soon as variceal bleeding is suspected. radiotherapy at present as an outpatient; this These drugs, which reduce portal blood has decreased his hypoglycaemic episodes. He pressure by constricting the splanchnic circula- is on oral feeds during the day. He needs occa- tion, have, if instigated early, been shown to sional nocturnal intramuscular glucagon for reduce rebleeding rates after a variceal bleed. hypoglycaemic episodes. Of the drugs available, terlipressin has also been shown to reduce mortality after an Final diagnosis episode of bleeding, whereas no improvement Non-islet cell tumour hypoglycaemia. in mortality has been documented for octre- otide, vasopressin, or somatostatin.2 1 Baxter RC, Holman SR, Corbould A, et al. Regulation of insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in non-islet cell tumour Q2: What was the cause of the rebleed hypoglycemia. J Clin Endocrinol Metab 1995;80:2700–8. and what procedure was performed? 2 Le Roith D, Clemmons D, Nissley P, et al. NIH Conference: The rebleed was due to gastric varices. A trans- insulin-like growth factors in health and disease. Ann Intern Med 1992;116:854–62. jugular intrahepatic portosystemic shunt

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(TIPSS) was performed. The radiograph in fig posthepatic circulation as in Budd-Chiari syn- Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from 1 (p 408) shows a portogram, with contrast drome, or to the prehepatic portal circulation filling the portal vein and outlining the stent, as in portal vein thrombosis. In the case which has been inserted to create a shunt discussed here, bleeding oesophageal varices between the portal and systemic circulation. were the presenting feature of chronic hepatitis Bleeding from gastric varices is diYcult to con- B infection. Oesophageal varices occur in 30% trol using conventional endoscopic techniques of compensated and 60% of decompensated and consequently TIPSS is recommended cirrhotic patients.1 The mortality from a early in their management.3 TIPSS works by variceal haemorrhage is 50% after the first providing a shunt from the portal system into bleed and 30% for each subsequent episode. the systemic venous system, thus decompress- Initial management of oesophageal variceal ing the portal system, and reducing portal haemorrhage is resuscitation and early endo- pressure. Gastric varices can also be treated therapy with either sclerotherapy or band liga- with direct endoscopic injection of tissue adhe- tion. Both techniques are eVective at control- sive agents such as cyanoacrylate, but although ling the initial bleed, but band ligation, where evidence shows that this is more eVective than the varices are obliterated by strangulation, has 5 conventional sclerotherapy, it has not been been shown to reduce bleed related mortality. compared with early TIPSS in a randomised Both procedures are technically diYcult, and controlled trial.4 even a skilled endoscopist will fail to achieve haemostasis in approximately 10% of cases, in Q3: What is the likely cause for the which case a balloon compression device such patient becoming drowsy, and how would as a Sengstaken tube should be inserted. you manage this? Vasoactive drugs have an additive eVect to The patient has developed encephalopathy. endoscopic treatment and should be instigated This is a complication, which occurs after at an early stage. TIPSS is recommended when endoscopic therapy has been attempted on two TIPSS, in around 35% of cases.4 Normally the separate occasions.3 The major complications liver metabolises compounds absorbed from that occur after TIPSS are stent stenosis which the bowel and prevents them from directly occurs in up to 60% of cases, and hepatic entering the systemic circulation (first pass encephalopathy which occurs in about 35% of metabolism). However, the TIPSS bypasses cases. Regular radiological assessment of the the liver and allows ammonium-containing stent with Doppler, or venography, is recom- compounds to enter the circulation. When mended to detect early stenosis, which if these compounds reach the brain they may act present can be treated with dilatation.4 as false neurotransmitters and interfere with Gastric varices do not respond as well to cerebral function. Encephalopathy is more treatment with conventional endoscopic tech- commonly a problem in patients with the most niques, such as banding or sclerotherapy, and severe liver disease, as subsequent metabolism consequently TIPSS has been advocated early (second pass) is also impaired. Most episodes in their management.3 Endoscopic injection of http://pmj.bmj.com/ of encephalopathy after TIPSS are short lived tissue adhesive into the site of bleeding has and the patient presented here recovered with been proved to reduce bleeding in the majority treatment after 48 hours. Treatment is with of cases, and oVers an alternative approach. lactulose which works by reducing the amount However, complications, which include em- of ammonium compounds produced by bacte- bolisation of the adhesive, may occur in up to 4 ria in the bowel. Treatment with a low protein 40% of cases and consequently the use of this diet can also be used to reduce the amino acid technique remains controversial.4

absorbed from the bowel, but this is controver- Acute variceal bleeding still carries a high on September 25, 2021 by guest. Protected copyright. sial, as many patients with variceal haemor- mortality, but it is hoped that new develop- rhage are already considerably malnourished at ments in management will lead to improved presentation. Treatment of encephalopathy outcome. The wide range of treatments should also include assessment for any possible currently available are likely to be optimally precipitating factors, such as sedating drugs, used if patients are managed by a multidiscipli- hypoglycaemia, hyponatraemia, renal failure, nary team, with access to intensive care, skilled further variceal haemorrhage, infection (in endosocopists, and interventional radiologists. particular spontaneous bacterial peritonitis), and subdural haematoma. Final diagnosis Gastrointestinal haemorrhage due to oesph- Discussion agogastric varices. Varices are dilated submucosal veins that project into the lumen of the gastrointestinal 1 D’Amico G, Pagliaro L, Bosch J. The treatment of portal tract. Ninety per cent occur in the oesophagus hypertension: a meta-analytic review. Hepatology 1995;22:332–54. with the majority of the remainder occurring in 2 Goulis J, Burroughs AK. Role of vasoactive drugs in the the gastric fundus. They form as a result of treatment of bleeding oesophageal varices. Digestion 1999; 60(suppl 3):25–34. raised pressure in the portal vein (portal hyper- 3 Grace ND, Groszmann RJ, Garcia-Tsao G, et al. Portal tension). The resulting portosystemic venous hypertension and variceal bleeding an AASLD single topic symposium. J Hepatol 1998;28:868–80. pressure gradient leads to varices forming at 4 Jalan R, Lui HF, Redhead DN, et al. TIPSS 10 years on. Gut the sites of anastomoses between the portal and 2000;46:578–81. 5 Laine L, Cook D. Endoscopic ligation compared with scle- systemic circulation. Portal hypertension is rotherapy for treatment of esophageal variceal bleeding. A commonly caused by hepatic cirrhosis, but may meta-analysis. Ann Intern Med 1995;123:280–7. also arise if there is obstruction to either the

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Recurrent pulmonary oedema in a 53 Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from year old woman Learning points x Always think of bilateral renal artery Q1: What is the most likely cause of this stenosis as a cause for recurrent pulmo- patient’s recurrent pulmonary oedema? nary oedema. Bilateral renal artery stenosis is a recognised x Hypertension on admission is a clue to cause of recurrent pulmonary oedema and is the diagnosis. the most likely cause of this patient’s symp- x Atherosclerosis of the renal and coronary toms. The severity of heart failure does not circulation occurring in the same patient correlate with the near normal left ventricular is relatively common. function. Hypertension on admission is a clue x Do not prescribe angiotensin converting to the diagnosis. enzyme inhibitors to treat the pulmonary oedema and hypertension in these Q2: What investigations should be patients—this may precipitate renal failure. performed next? x Renal vein renin sampling may play a part Diagnostic imaging tests are used to assess the in predicting the clinical outcome of location and severity of the disease; initial PTRA. screening for bilateral renal artery stenosis is by x Definitive treatment is revascularisation renal ultrasound, which may show small of the renal arteries, either by surgery or kidneys. Duplex Doppler sonography can also angioplasty. be used to measure blood flow velocities in the renal arteries. Confirmation of the lesions is by renal angiography (see fig 1), and more arterial disease.2 In our patient echocardio- recently magnetic resonance angiography. graphy at initial presentation showed mild Functional diagnostic tests, for example, renal impairment of left ventricular contraction vein renin sampling, can be used to assess the which did not correlate with the degree of heart pathophysiological importance of the stenoses. failure and the underlying diagnosis of bilateral renal artery stenosis was correctly identified Q3: What treatment options are available with PTRA being performed two years later. to this patient? Knowing which renal artery would benefit Definitive treatment is revascularisation of the from PTRA in cases of bilateral disease is renal arteries, either by surgery or more important. Diagnostic imaging tests, for exam- commonly percutaneous transluminal renal ple, angiography, can be used to assess the angioplasty (PTRA) with or without stent location and severity of the disease; in our case insertion (see fig 2). This woman underwent bilateral tight stenoses were seen. Functional PTRA to the right renal artery and remained diagnostic tests can then be used to assess the symptom free for five years after the procedure. pathophysiological importance of the lesions and in the case of renal vein renin measure- Discussion ments, this may be used to predict an improve- http://pmj.bmj.com/ This case illustrates the importance of recog- ment in clinical state after revascularisation. In nising bilateral renal artery stenosis as a cause hypertension due to unilateral renal artery ste- of recurrent pulmonary oedema in the pres- nosis, renal vein renin measurements diVering ence of coronary artery disease. It is vital not to by a factor of 1.5:1 or more (higher value from assume that the coronary artery disease is the aVected side) have a predictive value of causative factor of the pulmonary oedema. It is improving blood pressure and symptoms by not surprising to find atherosclerotic involve- revascularisation in 90% of cases.3 In bilateral

ment of both renal and coronary arteries in the disease, the renal vein renin values can often on September 25, 2021 by guest. Protected copyright. same subject and previous series have shown show asymmetry, similar to patients with this.1 Other authors have also shown recurrent unilateral disease with the higher value pulmonary oedema to occur with isolated renal corresponding to the side with the more severe stenosis. The explanation for this asymmetric

Figure 1 Renal angiogram showing tight renal artery stenosis of right kidney. Figure 2 Renal angiogram after PTRA and stent insertion.

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pattern is presumed to be the same as for Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from unilateral disease and is due to the fact that one Box 2: Clinical manifestations of side is more severely aVected than the other.4 clostridial septicaemia The less ischaemic kidney is exposed to a higher x Asymptomatic. perfusion pressure than the other kidney and x Pyrexia. this tends to suppress renin secretion. In cases x Septic shock. of bilateral disease the more severely aVected x Spreading cellulitis. kidney has the highest renin activity and PTRA x Myonecrosis (gas gangrene). to this side has been shown to improve clinical x Acute haemolytic anaemia. outcome in some patients with hypertension,5 x Acute renal failure. though not in all.56 Our patient underwent x Disseminated intravascular coagulation. 4 renal vein sampling from the inferior vena cava x Neutropenic enterocolitis. which showed a left:right ratio of 1:2.33. x Gastrointestinal haemorrhage. PTRA to the right renal artery was performed x Bowel perforation and peritonitis. 5 and this conveyed symptomatic benefit for a x Liver and brain abscess. number of years after the procedure.

Final diagnosis Clostridial bacteraemia occurs in the context of Bilateral renal artery stenosis. malignancy (gastrointestinal, genitourinary, haematological) with or without chemotherapy 1 Meissner MD, Wilson AR, Jessup MJ. Renal artery stenosis and radiotherapy, neutropenia, diabetes melli- in heart failure. Am J Cardiol 1988;64:1307–8. tus, severe atherosclerotic disease, steroid use, 2 Pickering TG, Devereux RB, James GD, et al. Recurrent pulmonary oedema in hypertension due to bilateral renal organ failure, etc. However clostridial bacterae- artery stenosis: treatment by angioplasty or surgical mia especially by non-histotoxic species can be revascularisation. Lancet 1988;ii:551–2. 3 Wilson JD, Braunwald E, Isselbacher RG, et al. Harrison’s spontaneous, transient, and asymptomatic and principles of internal medicine. 12th Ed. New York: McGraw Hill, 1988: 1192–230. may not correlate with the clinical picture. The 4 Bremmer BM, Rector Fc Jr. The kidney. 4th Ed. source of clostridia bacteraemia could be Philadelphia: WB Saunders, 1991: 1920–54. traced to uterine cavity, skin, gastrointestinal 5 Pickering TG, Sos TA, James GD, et al. Comparison of renal vein renin activity in hypertensive patients with stenosis of tract, genitourinary tract, or lung. both renal arteries. J Hypertens 1985;3(suppl 3):291–3. 6 Derx FHM, Schalekamp MADH. Renal artery stenosis and The severe manifestations of clostridial sep- hypertension. Lancet 1994;344:237–9. sis generally occur with the histotoxic species (perfringens, septicum, and novyi) and is due to the elaboration of alpha toxin which is a A case of unusual septicaemia phospholipase C capable of hydrolysing leci- thin and sphingomyelin in cell membranes, and Q1: What is the finding in the barium cause massive intravascular haemolysis. enema? The clinical manifestations are listed in box 2. The barium enema (see p 409) shows a huge The mainstays of treatment include prompt antimicrobial therapy (penicillin, metronida- filling defect in the caecal region suggesting http://pmj.bmj.com/ malignancy. zole, clindamycin, etc) surgical debridement of necrotic tissues and drainage of abscesses. Q2: What is the association between the Hyperbaric oxygen may be an important adju- barium enema finding and septicaemia vant when tissue necrosis is a major compo- referred to? nent. The mortality can be as high as The Gram positive anaerobic organism is of the 50%–70%. clostridial genus. In this case is it was Clostrid- ium septicum. There is a well recognised associ- Box 3: Learning points on September 25, 2021 by guest. Protected copyright. ation between clostridial bacteraemia and x Clostridial bacteraemia especially colonic malignancy. septicum necessitates a search for gastro- intestinal and haematological malig- Discussion nancies as there is a strong association. Clostridial bacteraemia is rare and in one study x Though it can be asymptomatic and it was found in only 0.3% of all blood cultures.1 transient, it can be rapidly fatal when Bacteraemia especially in the context of malig- associated with septic shock, nancy can be monomicrobial or polymicro- myonecrosis, haemolytic anaemia, and bial.2 Clostridia are ubiquitous organisms that disseminated intravascular coagulopathy. are normally found in the gastrointestinal and x It should be promptly recognised and female genital tracts. Clostridial species can be treated on suspicion. divided into histotoxic and non-histotoxic. Three main factors seem to predispose to the development of clostridial sepsis (box 1).3 Final diagnosis Clostridial septicaemia due to caecal carcinoma. Box 1: Predisposing factors for clostridial bacteraemia 1 Gorbach SL, Thadepalli H. Isolation of clostridium in x Abnormal local milieu with a decreased human infections: evaluation of 114 cases. J Infect Dis 1975; 131:s81–8. oxidation-reduction potential. 2 Bodey GP, Rodriguez S, Fainstein V et al. Clostridial x Systemic immunosuppression. bacteremia in cancer patients. A 12-year experience. Cancer 1991;67:1928–42. x Epithelial barrier disruption. 3 De Virgilio C, Klein S, Chang L, et al. Clostridial bacteremia: implications for the surgeon. Am Surg 1991;57: 388–93.

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4 Wade DS, Nava HR, Douglass HO Jr. Neutropenic entero- Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from colitis. Clinical diagnosis and treatment. Cancer 1992;69: Learning points 17–23. 5 Cheng YT, Huang CT, Leu HS et al. Central nervous x Riedel’s thyroiditis is a rare cause of system infection due to Clostridium septicum: a case report hypothyroidism. and review of the literature. Infection 1997;25:171–4. x The condition is characterised by the presence of a stony hard or woody thyroid. Hydronephrosis and a hard neck swelling x 15% of cases of retroperitoneal fibrosis are associated with other fibrotic Q1: What is the likely diagnosis based on processes such as Riedel’s thyroiditis, the computed tomogram appearance? sclerosing cholangitis, ocular This appearance is highly suggestive of retro- pseudotumour, and mediastinal fibrosis. peritoneal fibrosis, although sarcoma and x Steroids and tamoxifen may be useful in lymphoma are also possibilities. halting the progression of the disease. The patient underwent a stenting procedure of the right ureter, which improved the hydronephrosis. She subsequently underwent a reported in the literature, and the concept of a ultrasound guided biopsy of the periaortic syndrome of Multifocal fibrosclerosis has been tissue, and histological examination confirmed described.5 This comprises multiple fibrotic fibrotic material with no evidence of malig- processes frequently occurring simultaneously nancy. in diVerent organ systems. Such conditions include Riedel’s thyroiditis, retroperitoneal Q2: What is the link with the thyroid fibrosis, sclerosing cholangitis, ocular pseudo- abnormality? tumour, and mediastinal fibrosis. It is esti- “Stony hard” or “woody” thyroid enlargement mated that around 15% of cases of retroperito- is characteristic of Riedel’s thyroiditis. This is a neal fibrosis are associated with fibrosis around condition characterised by invasion of the thy- other structures.6 roid and adjacent structures by a dense The pathogenesis of the Riedel’s thyroiditis fibrosclerotic process. It is a rare cause of is unclear. An autoimmune aetiology has been hypothyroidism, but a clear association with hypothesised by the observations of an other sclerotic processes is reported, including eosinophilic infiltrate on histological examina- idiopathic retroperitoneal fibrosis (see below). tion, the common presence of thyroid auto- As the patient was asymptomatic and not keen antibodies, and frequent association with other to undergo an open biopsy of the thyroid, this autoimmune conditions such as pernicious procedure was not undertaken. A fine needle anaemia, Addison’s disease, and hypopara- aspirate of the thyroid was not attempted as thyroidism. It is of note, however, that the commonly they yield a dry tap in Riedel’s thy- fibrosis seen in Riedel’s thyroiditis is commonly roiditis. In view of the progressive nature of not just limited to the thyroid, but also invades idiopathic retroperitoneal fibrosis, and its other structures within the neck, suggesting a http://pmj.bmj.com/ reported response to steroids, a moderate dose primary fibrotic process starting in the neck, of oral prednisolone has recently been started rather than a tissue specific autoimmune by this patient. Within one month of com- condition. mencing the steroids, she felt less tired, her More recently, it has been suggested that goitre reduced in size, and the erythrocyte retroperitoneal fibrosis is an autoallergic reac- sedimentation rate fell to 10 mm/hour. tion to the lipid components of atherosclerotic plaques within the aorta, leading to fibrosis

Discussion around the aorta. Furthermore, it has been on September 25, 2021 by guest. Protected copyright. In 1885, Bowlby described a necropsy finding hypothesised that Riedel’s thyroiditis may be a of a hard infiltrative mass around thyroid periarteritis of the carotid artery resulting in invading other structures in the neck.1 He pre- cervical fibrosis subsequently involving the sumed this was sarcomatous change within the thyroid, and thus the conditions may have a thyroid with local invasion. Subsequently similar pathogenesis, accounting for their com- Riedel described a case of invasive fibrous thy- mon coassociation.7 roiditis which he termed Riedel’s struma.2 He Treatment of Riedel’s thyroiditis and retro- described the consistency of the swelling as peritoneal fibrosis is essentially anecdotal, due eisenharte strumitis, to emphasise the stony hard to the rarity of the condition. As in our patient, or woody nature of the thyroid on palpation. steroids have been used successfully to induce Riedel’s thyroiditis is an unusual cause of resolution of the fibrotic process in some cases, hypothyroidism and goitre. In a series of particularly where compressive complications 56 000 thyroidectomies from the Mayo Clinic, of the trachea or ureters is present.8 It is of only 37 were found to have histological note, however, that spontaneous resolution has evidence of the condition.3 The condition is also been reported. A further drug that may be commonly insidious in onset, and may be of benefit in Riedel’s thyroiditis and retroperi- asymptomatic. toneal fibrosis is tamoxifen, which induces The association of Riedel’s thyroiditis with transforming growth factor-â, which is in turn other fibrotic processes was first described in an inhibitor of fibroblast growth factor.910 1963, when a case of Riedel’s thyroiditis was In summary therefore, we present a patient reported in association with retroperitoneal who presented initially with symptomatic fibrosis, again from the Mayo Clinic.4 Subse- hypothyroidism and a hard thyroid swelling quently, around a dozen cases have been compatible with Riedel’s thyroiditis, in whom a

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proved diagnosis of retroperitoneal fibrosis has Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from been made. The co-occurrence of two or more Learning points Primary non-Hodgkin’s lymphoma is an fibrotic processes in diVerent organs is a rare, x uncommon malignancy of the thyroid but well described association, and patients gland and is usually, although not presenting with one such condition may well invariably, preceded by Hashimoto’s have evidence of fibrosis elsewhere. thyroiditis. x It is very easily mistaken for anaplastic Final diagnosis thyroid carcinoma on histology. Retroperitoneal fibrosis associated with Immunohistochemical stains are very Riedel’s thyroiditis. x important in distinguishing between the two conditions as treatment and 1 Bowlby AA. Infiltrating fibroma (?sarcoma) of the thyroid prognosis is entirely di erent. gland. Trans Pathol Soc Lond 1885;36:420. V 2 Riedel BMCL. Die chronische, zur Bildung eisenharter x Prognosis of this form of lymphoma is Tumoren fuhrende Entzundung der Schilddruse. Verhand- usually good as it responds well to lung Der Deutschen Gesellschaft fur Chirurgie 1896;25:101–5. 3 Hay ID. Thyroiditis: a clinical update. Mayo Clin Proc 1985; radiotherapy and chemotherapy. 60:836–43. 4 Bartholomew LG, Cain JC, Woolner LB, et al. Sclerosing cholangitis. Its possible association with Riedel’s struma and fibrous retroperitonitis—report of two cases. N Engl J Med 1963;269:8–12. lymphoma. The other rare diVerential diagnosis 5 Gleeson MH, Taylor S, Dowling RH. Multifocal fibrosclero- sis. Proc R Soc Med 1970;63:1309–11. is Riedel’s thyroiditis, which would be excluded 6 Amis SE. Retroperitoneal fibrosis. Am J Radiol 1991;157: by open biopsy of the thyroid gland. 321–9. 7 de Boer WA, van Coevorden F, Wiersinga WM. A rare case of Riedel’s thyroiditis, 6 years after retroperitoneal fibrosis: Q3: What is a common predisposing two diseases with one pathogenesis? Neth J Med 1992;40: 190–6. factor? 8 Bagnasco M, Passalacqua G, Pronzato C, et al. Fibrous Autoimmune Hashimoto’s thyroiditis has usu- invasive (Riedel’s) thyroiditis with critical response to steroid treatment. J Endocrinol Invest 1995;18:305–7. ally, although not invariably, been known to 9 Few J, Thompson NW, Angelos P, et al. Riedel’s thyroiditis: predispose to this form of lymphoma. treatment with tamoxifen. Surgery 1996;120:993–9. 10 Owens LV, Cance WG, Huth JE. Retroperitoneal fibrosis treated with tamoxifen. Am Surg 1995;61:842–4. Q4: What is the treatment and prognosis of this condition? Non-Hodgkin’s lymphoma of the thyroid gland A woman with an abnormal mass in the usually responds well to a combination of thyroid gland radiotherapy and chemotherapy or radio- therapy alone in localised stage 1 disease. The Q1: What other investigations would you treatment of choice, however, is total thyroid- consider? ectomy plus radiotherapy in patients where Peak expiratory flow measurement would give radical surgery is possible. Prognosis of this an objective assessment of tracheal stenosis by uncommon malignancy is usually good and demonstrating extrathoracic airways obstruc- much better than anaplastic thyroid carcinoma http://pmj.bmj.com/ tion. and hence every eVort must be made to distin- Computed tomography of the neck was also guish the two forms of malignancy. carried out and revealed a heterogenous mass lesion arising from the left lobe of the thyroid Discussion gland surrounding the trachea, left common Primary thyroid lymphoma is an uncommon carotid artery, and extending retrosternally disease representing 5% of all thyroid neo- with patchy contrast enhancement. There was plasms and the majority are due to non- 1 no evidence of lymphadenopathy. The tumour Hodgkin’s lymphoma. They aVect elderly on September 25, 2021 by guest. Protected copyright. was far too advanced for a thyroidectomy and patients (median age at presentation 61–73 hence only an open biopsy and tracheostomy years) and the reported female:male ratio could be performed (normally, removal of a varies from 2.6:1 to 8.4:1.23 Though it is wedge of thyroid tissue down to the trachea is widely accepted that the vast majority of suYcient to relieve airways obstruction without thyroid lymphomas occur with the background resorting to tracheostomy). of autoimmune Hashimoto’s thyroiditis (either by the clinical history, histology, or serology), Q2: What is the diagnosis and what is it its presence has been reported as varying from commonly mistaken for? 22%–100% and is by no means suYcient to Histology confirmed a highly malignant tumour establish a diagnosis.4 In recent years the extensively infiltrating the thyroid gland with recognition of mucosa associated lymphoid tis- extrathyroidal spread without any evidence of sue (MALT) has drawn new attention to the papillary or follicular diVerentiation. This ap- pathogenesis of primary lymphomas of thyroid. pearance was initially thought to be due to ana- MALT lymphomas are also known to trans- plastic thyroid carcinoma, with which it is com- form into high grade lymphomas.4 monly mistaken. However, immunohisto- Typically, the disease presents with a rapidly chemical stains revealed positive staining for growing, painless thyroid mass with or without lymphoid cells and negative for epithelial cells. obstructive symptoms and variable thyroid Tumour cells had centroblastic morphology and dysfunction. Brownlie et al reported eight such were CD20, CD79a positive (CD3 negative) cases over a 12 year period: one of them indicating a B-cell phenotype. Also, the prolif- was thyrotoxic and the other hypothyroid.5 eration fraction, as indicated by the high MIB-1 Matsuzuka et al found 27% of their patients to staining, confirmed a high grade non-Hodgkin’s be hypothyroid and 14% had evidence of

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subclinical hypothyroidism on the basis of 7 Skarsgard ED, Connors JM, Robins REA. Current analysis Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from 6 of primary lymphoma of the thyroid. Arch Surg 1991;126: coexistence of Hashimoto’s thyroiditis. 1199–203 (discussion 1203–4). According to Skarsgard et al, using log rank survival tests, statistically significant predictors of improved survival were tumour mass less A hungry baby fails to thrive than 10 cm, absence of dysphagia at presentation/mediastinal lymphadenopathy, 7 Q1: What is the diagnosis? and disease localised to the thyroid gland. The diagnosis is neonatal diabetes mellitus, Treatment of choice is total thyroidectomy plus which is defined as persistent hyperglycaemia radiotherapy in patients where radical surgery in term infants, within the first six weeks of life, is possible or radiotherapy alone, which usually 1 requiring insulin for two or more weeks. Alter- yields good results. Most studies recommend native names are temporary idiopathic neona- combined radiotherapy and chemotherapy for tal hyperglycaemia, neonatal pseudodiabetes localised thyroid lymphoma and radiotherapy mellitus, transient diabetes of early infancy, alone for a small select group of patients with and congenital temporary diabetes mellitus.1 stage I disease and a small tumour bulk. Though there was no histological evidence of Q2: What is the likely long term outcome? Hashimoto’s thyroiditis in our patient (lym- Neonatal diabetes diVers from insulin depend- phomatous growth had completely replaced ent (type I) diabetes in that it has a highly vari- the whole of the thyroid gland), she had able course. About half of these infants have biochemical evidence of subclinical hypo- permanent diabetes, and half have a period of thyroidism and strongly positive thyroperoxi- remission, although 65% of the transient forms dase antibodies, which may be indicative of subsequently become diabetic again.2 The thyroiditis in the absence of a direct histological transient and permanent forms can only be proof. Additionally, she had evidence of other distinguished by their clinical course.1 Infants autoimmune diseases namely, vitligo and insu- with the transient form usually become eugly- lin dependent diabetes, both of which highlight caemic without insulin treatment within the the autoimmune background that could have first year.3 been instrumental in triggering her primary pathology. It has been quoted that whenever Q3: What is the genetic linkage to this there is no previous evidence of Hashimoto’s condition? thyroiditis the typical presentation of primary Molecular DNA analysis testing of infants with thyroid lymphoma may be taken as suggestive 4 transient neonatal diabetes has recently shown of anaplastic thyroid carcinoma. Even histo- a paternal uniparental disomy of chromosome logically, anaplastic thyroid carcinoma is virtu- 6. This refers to the inheritance of both 6th ally indistinguishable from high grade non- chromosomes from one parent only, with no Hodgkin’s lymphoma on a haematoxylin and contribution from the other. The findings pre- eosin stained section, hence a battery of dict that transient neonatal diabetes is due to immunohistochemical stains are needed to the overexpression of an imprinted gene at http://pmj.bmj.com/ establish the exact histogenesis of the tumour 6q22-23.4 cells so that proper treatment can be instituted immediately. Outcome This form of lymphoma responds well to He was initially managed in the paediatric treatment and has a much better prognosis intensive care unit with sedation, mechanical than anaplastic carcinoma, as is evident from ventilation, plasma volume expansion (human the excellent results in our patient. She has

plasma protein fraction and saline), intra- on September 25, 2021 by guest. Protected copyright. received radiotherapy and is currently under- venous insulin infusions, and anticonvulsants going chemotherapy and has done very well so to control seizure activity. He was discharged far with regression of her neck swelling and home after three weeks when he was feeding complete resolution of her symptoms, mainly well and on a twice daily subcutaneous insulin dysphagia, hoarseness, and stridor. regimen. At 15 months his developmental milestones were all normal, and he remained Final diagnosis on insulin with no apparent hypoglycaemic High grade non-Hodgkin’s lymphoma. episodes.

1 Stolfi VM, Rossi P, Bacaro D, et al. Primary lymphoma of Discussion the thyroid gland. Review of the literature and presentation Only 0.5% of paediatric patients with diabetes of a clinical case. G Chir 1989;10:641–5. 1 2 Devine R, Edis A, Banks P. Primary lymphoma of the develop the disease during the first year of life. thyroid: a review of the Mayo clinic experience through Neonatal diabetes mellitus is one of the rarest 1978. World J Surg 1981;5:33–8. 3 Pedersen R, Pedersen N. Primary non-Hodgkin’s forms of diabetes, with a reported incidence of lymphoma of the thyroid gland: a population based study. 1 in 450 000 live births.2 In Northern Ireland, Histopathology 1996;28:25–32. 4 Fonseca E, Sambade C. Primary lymphomas of the thyroid one case presents approximately every 16 gland—a review with emphasis on diagnostic features. Arch years. Anat Cytol Pathol 1998;46:94–9. 5 Brownlie BE, Fitzharris BM, Abdelaal AS, et al. Primary Babies with neonatal diabetes are classically thyroid lymphoma: clinical features, treatment and small for dates, term infants, as found in the outcome: a report of 8 cases. NZMedJ1994;107:301– 4. case presented. They develop hyperglycaemia 6 Matsuzuka F, Miyauchi K, Katayama S, et al. Clinical and marked metabolic acidosis with severe aspects of primary thyroid lymphoma: diagnosis and dehydration (as shown in this case with low treatment based on our experience of 119 cases. Thyroid 1993;3:93–9. pH, low bicarbonate, and compensatory low

www.postgradmedj.com Self assessment answers 421 Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from 5 Hermann R, Laine AP, Johansson C, et al. Transient but not Learning points permanent neonatal diabetes mellitus is associated with paternal uniparental isodisomy of chromosome 6. Pediatrics x Neonatal diabetes mellitus is rare (1 in 2000;105:49–52. 450 000 births). x The majority of babies eventually have permanent diabetes. An unusual case of diarrhoea and weight x Genetic linkage has been shown to unipa- loss rental disomy of chromosome 6. Q1: What is the diVerential diagnosis? The extremely low serum cortisol concentra- carbon dioxide, from hyperventilation). The tion, which failed to rise in response to event here may have been precipitated by an tetracosactrin confirms adrenal failure. A intercurrent viral infection, manifested by the normal adrenal response to tetracosactrin is high white cell count and platelets. considered to be an increase in serum cortisol Seventy five per cent of cases first present concentration to a peak exceeding 550 nmol/l. with symptoms within 10 days of birth.1 The However, this failure may be primary (Addi- picture of a lively, alert but grossly dehydrated son’s disease), secondary to a pituitary lesion infant is classical, in contrast to the semicoma- or, very rarely, tertiary (hypothalamic). Failure tose state and glazed eye appearance of severely of the adrenal gland to respond to tetracosac- dehydrated infants. Polyuria is diYcult to trin by increasing production of cortisol may be recognise in the newborn. Rapid rehydration, observed in all forms of adrenal failure: in pri- in the presence of hypernatraemia (sodium 154 mary adrenal failure due to destruction of the mmol/l), can cause cerebral oedema and adrenal gland itself (for example, due to subsequent seizure activity, if serum sodium autoimmune adrenalitis, infarction, or tuber- falls too quickly. Balancing the correct fluid culosis) and in secondary and tertiary adrenal replacement over the first hours of the acute failure due to atrophy of the gland as a result of period requires very close monitoring of blood insuYcient stimulation by adrenocortico- electrolytes. With few exceptions, most infants trophic hormone (ACTH, corticotrophin). require exogenous insulin. After initiation of Conversely, a normal cortisol response in the insulin therapy, weight gain usually accelerates. short tetracosactrin test cannot exclude sec- Various suggestions to explain the pathogen- ondary adrenal insuYciency. esis of this condition have been proposed, including reduced insulin production from Q2: What further investigations would pancreatic dysmaturity, insulin resistance,3 and you request? insulinopenia from a poor response of the pan- Serum ACTH concentration measured at 9 creatic beta cell to hyperglycaemia.1 The fact am, 24 hours after his previous dose of hydro- that most babies are low birth weight may be cortisone, was inappropriately low (12 ng/l, related to the failure of insulin secretion, as reference range 5–36) compared with paired insulin is one of the main growth factors in serum cortisol concentration (56 nmol/l), sug- http://pmj.bmj.com/ utero.4 Heredity plays an important part as gesting secondary (or possibly tertiary) adrenal approximately 25% of neonatal cases have an failure (fig 1). This was further investigated aVected sibling, with boys and girls being with a Depot Synacthen test (tetracosactrin equally aVected.1 It has been suggested that the two phenotypes of transient and permanent 3000 neonatal diabetes have diVerent genetic back- grounds, as the paternal uniparental disomy of 1000 700 chromosome 6 on DNA analysis, found in on September 25, 2021 by guest. Protected copyright. some cases with the transient form, has not 500 been shown in the permanent form of neonatal 300 diabetes.5 The overall outcome for general health and 100 normal intellectual development is usually 70 good. Complications of vasculopathy in long 50 term follow up reports are rare.12The progno- 30 sis is worst in permanent diabetes, onset of diabetes after 1 month of age, and associations 10 Plasma corticotrophin (pg/ml) with other rarer associated syndromes 7 (Wolcott-Rallinson syndrome and X linked 5 2 3 hyperuricaemia). 0.3 0.5 0.7 1 357 10 30 50 Plasma cortisol (µg/dl) Final diagnosis Neonatal diabetes mellitus. Figure 1 Plasma cortisol concentration as a function of plasma ACTH (corticotrophin) in normal subjects (filled circles), patients with primary adrenal failure (either 1 Fosel S. Transient and permanent neonatal diabetes. Eur J untreated or 24 hours after last dose of hydrocortisone; open Pediatr 1995;154:944–8. circles), and patients with pituitary disease with or without 2 Von Muhlendahl KE, HerkenhoV H. Long-term course of adrenal insuYciency (triangles). A cross indicates the neonatal diabetes. N Engl J Med 1995;333:704–8. present case. To convert cortisol concentrations from µg/dl 3 Shield JPH, Baum JD. Transient neonatal diabetes and later into SI units (nmol/l), multiply by 27.6 and to convert onset diabetes: a case of inherited insulin resistance. Arch Dis Child 1995;72:56–7. ACTH (corticotrophin) from pg/ml to pmol/l, multiply by 4 Shield JPH, Gardner RJ, Wadsworth EKJ, et al. Aetiopathol- 0.2202. Figure after Oelkers (N Engl J Med ogy and genetic basis of neonatal diabetes. Arch Dis Child 1996;335:1206–12). Copyright 1996 Massachusetts Fetal Neonatal Ed 1997;76:F39–42. Medical Society. All rights reserved.

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with zinc phosphate complex; 1 mg Depot Postgrad Med J: first published as 10.1136/pmj.77.908.412e on 1 June 2001. Downloaded from Synacthen given at 8 am each morning for four Learning points mornings). Serum cortisol concentrations in- x Secondary adrenal failure is easily missed creased from a baseline before the dose of 33 since many of the classical symptoms of nmol/l on the first morning to concentrations Addison’s disease are absent. after the dose of 174, 451, 521, and 520 nmol/l x The short tetracosactrin (Synacthen) test on the first to fourth mornings respectively, does not discriminate between primary, confirming that his adrenal would respond to secondary, or tertiary adrenal failure. sustained ACTH stimulation with stepwise x Secondary, as well as primary, adrenal increments in cortisol production. This test failure may have autoimmune associa- confirmed that his adrenal failure was second- tions. ary to either a pituitary or hypothalamic lesion. Magnetic resonance imaging (MRI) with con- trast was entirely normal, showing no focal lesion in the pituitary or hypothalamus. Given to be the most likely diagnosis in the present the normal MRI, further testing to discrimi- case. However, many of the common features of nate between secondary or tertiary adrenal primary adrenal failure (for example, hyperpig- failure was deemed clinically unnecessary. mentation, hyponatraemia, hyperkalaemia, urae- mia, and adrenal antibodies) were absent. This raised the possibility of secondary (or tertiary) Q3: How would you manage the patient? Patients with acute adrenal insuYciency re- adrenal failure, which was confirmed by the quire immediate treatment with intravenous demonstration of an inappropriately low ACTH hydrocortisone and correction of any fluid or and an adequate adrenal response to sustained electrolyte deficit. In the long term, patients corticotrophin stimulation. with primary adrenal failure will require On the basis of normal pituitary and replacement of both the glucocorticoid and hypothalamic anatomy on imaging, normal mineralocorticoid components of adrenal ster- serum prolactin, an intact pituitary-gonadal oid production. Consequently the patient axis and intact thyrotroph response to primary received hydrocortisone (30 mg/day in a thyroid failure, the diagnosis of isolated ACTH divided dose: 20 mg am, 10 mg pm) and deficiency was established. This is a rare cause of adrenal failure with less than 200 cases hav- fludrocortisone (50 µg/day). Fludrocortisone 2 was discontinued when the diagnosis of ing been reported in the literature by 1990. secondary adrenal failure was confirmed, since Although histological confirmation is lacking, the mineralocorticoid pathway is intact in sec- it is possible that our patient had lymphocytic ondary adrenal failure. After the institution of hypophysitis, a rare inflammatory lesion of the treatment, the patient felt much better (“10 pituitary gland which can cause autoimmune destruction of one pituitary cell line with years younger”); his dizziness (blood pressure 3 140/90 mm Hg lying and standing), diarrhoea, resultant failure of the target organ. This con- and anaemia completely resolved. His appetite dition is commonly associated with autoim- 34 http://pmj.bmj.com/ improved and over several months his weight mune thyroid disease and is far commoner in rose to 81 kg. women than men. In summary, our case demonstrates the diY- culty of recognising the clinical features of sec- Discussion Clinical features which are due to cortisol ondary adrenal failure and of establishing the deficiency are common to both primary and diagnosis biochemically. Finally, it is important secondary causes of adrenal failure and, as in the to remember that other autoimmune disease may be associated with secondary, as well as present case, can include weight loss, anorexia, on September 25, 2021 by guest. Protected copyright. diarrhoea, decreased libido and potency, and a primary, adrenal failure. normocytic anaemia. Postural hypotension oc- curs in both primary and secondary adrenal fail- Final diagnosis ure, despite the fact that the mineralocorticoid Isolated ACTH deficiency. axis is intact in the latter. This eVect is explained by the requirement of adrenaline (epinephrine) 1 Oelkers W. Adrenal insuYciency. N Engl J Med synthesis for high local concentrations of cortisol 1996;335:1206–12. 2 Sauter NP, Toni R, McLaughlin CD, et al. Isolated adreno- in the adrenal medulla and the decreased corticotropin deficiency associated with an autoantibody to a corticotroph antigen that is not adrenocorticotropin or expression of vascular catecholamine receptors other proopiomelanocortin-derived peptides. 1 J Clin Endocri- in secondary adrenal failure. nol Metab 1990;70:1391–7. 3 Laing I, McWilliam L, Owen D, et al. Secondary adrenal Primary hypothyroidism is commonly associ- failure in a young woman presenting as hypoglycaemic ated with primary adrenal failure as part of the coma. Ann Clin Biochem 1998;35:545–8. type II autoimmune polyglandular syndrome 4 Thodou E, Asa SL, Kontogeorgos G, et al. Lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol (Schmidt’s syndrome) and initially this was felt Metab 1995;80:2302–11.

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