In our patient the diagnosis of small intestinal bacterial overgrowth was based on the clin ical syndrome of steatorrhoea, weight loss, and vitamin B12 deficiency, with small intestin al diverticulosis and a rapid response to antibiotics. 10d) How would you manage this patient? Any predisposing factors should be corrected, but this is rarely possible, especially for a natomical abnormalities. Nutritional deficiencies should be corrected. In addition to vitam in B12 deficiency, fat-soluble vitamins A, D, and E may be deficient. Vitamin K is produced by bacteria and not deficient in these patients. Thiamine and nicotinamide may rarely be d eficient. Antibiotic therapy is highly effective in the treatment of small intestinal bacte rial overgrowth. Metronidazole 400mg three times daily, or ciprofloxacin 500mg twice daily for a week, is usually effective. Cyclical (occasionally continuous) antibiotics, for 1 wee k every month, alternat- ing between these antibiotics is an appropriate way of managing pa tients with abnormal anatomy. We managed our patient on 1 week of antibiotics per month, alternat- ing between ciprofloxa cin and metronidazole. She had an excellent response with resolution of symptoms and stabil ization of her weight. After 14 months we decided to stop the antibiotics because she was w ell. OXFORD CASE HISTORIES 66 Seven months later she remained well off antibiotics, but relapse at some stage can be expe cted. 10e) Discuss the underlying condition Small intestinal diverticulosis is uncommon and although autopsy series report a prevalence of 0.06 \200\2231.3%, the true prevalence is unknown. It occurs more frequently with advan cing age and the peak clinical prev- alence is in the 6th and 7th decades of life. Most div erticula (80%) are jejunal. In general diverticula become fewer and smaller more distally. An association between small bowel and colonic diverticula has been postulated, but the lat ter are almost universal with advancing age. Small bowel diverticula are thought to represe nt herniation of mucosa and sub-mucosa through the muscle layers of the intestine, on the m esenteric border. Unlike colonic diverticula, acute emergencies from diverticulitis, perfor ation, or hemorrhage are exceptionally uncommon. Further reading Rana SV, Bhardwaj SB (2008). Small intestinal bacterial overgrowth. Scand J Gastroenterol; 43: 1030 \200\22337. Khoshini R, Dai SC, Lezcano S, Pimentel M (2008). A systematic review of diagnostic tests for small intestinal bacterial overgrowth. Dig Dis Sci; 53: 1443 \200\22354. Kassahun W, Fangmann J, Harms J, Bartels M et al. (2007). Complicated small-bowel diverticu losis: A case report and review of the literature. World J Gastroenterol; 13: 2240 \200\223 42. CASE 11 67 Case 11 A 53-year-old unemployed man with known alcoholic liver cirrhosis presented to the emergenc y department with jaundice, ascites, and oedema to the thighs. He reported drinking 6 pints of beer/day for over 30 years. He was not on any medication. On examination, the pulse rate was 88bpm and blood pressure 120/60mmHg. There was firm hepa tomegaly, with the liver edge palpable 6cm below the cos- tal margin, and definite ascites. There was no asterixis, but multiple spider naevi were present. Investigations showed: mol/L Na 123mmol/L, K 3.7mmol/L, urea 2.0mmol/L, creatinine 93 mol/L, ALT 133 IU/L, ALP 708 IU/L, albumin 22g/L Bilirubin 235 CRP 26mg/dL Prothrombin time 17.0 sec Abdominal ultrasound: course liver texture, splenomegaly, and ascites. He was started on chlordiazepoxide and intravenous thiamine. A diagnostic (20ml) ascitic ta p was carried out, which showed no evidence of spontaneous bacterial peritonitis. He had hi gh gradiant ascites (Serum-ascites albumin gradient >11g/L). Two days after admission, he developed severe cellulitis in his right leg. He was started o n intravenous ceftriaxone. The next day his creatinine had risen to 266 mol/L, with the bi lirubin increasing to 300 mol/L. Moderate confusion developed and the blood pressure decre ased to 100/50mmHg. Questions 11a) What are the possible causes of the decline in renal function? 11b) What is the pathophysiology of renal dysfunction in chronic liver disease? 11c) What management should be instituted? 11d) His ascites became very uncomfortable. What would you recommend? OXFORD CASE HISTORIES 68 Answers 11a) What are the possible causes of the decline in renal function? As in any case of acute renal failure, pre-renal, renal, and post-renal causes need to be c onsidered. Specific to patients with liver disease, hepatorenal syndrome (in the pre-renal category) should always be considered. The two most likely causes in this particular case are both pre-renal in origin. Sepsis fro m cellulitis causing hypovolaemia and therefore decreased renal perfusion may be the sole c ause or there may be underly- ing hepatorenal syndrome. A normal creatinine at presentation does not exclude underlying renal dysfunction. Patients with liver cirrhosis often have ap parently normal renal function, because the creatinine is not a good marker of glomerular f iltration rate in such patients. The creatinine is \200\230falsely \200\231 low because of decreased hepatic creatinine synthesis and decreased skeletal muscle mass. Other pre-renal and renal causes in the presence of cirrhosis should be considered. These i nclude spontaneous bacterial peritonitis, excessive diuretic use, hypovolaemia from gastroi ntestinal bleeding, dehydration, and renal tubular damage from nephrotoxic drugs, or contra st agents. None of these causes were present in this case. There are multiple causes of int rinsic renal failure. In order to differentiate any cause of pre-renal failure or hepatorenal syndrome from intri nsic renal failure, a urinary sodium should be per- formed. It should be <10mmol/L in the f ormer two conditions (due to avid sodium retention by functioning renal tubules) and >30mmo l/L in intrinsic renal failure (attributable to renal tubular dysfunction). Urine microscop y is likely to show urinary casts or cellular debris in intrinsic renal disease. IgA nephro pathy can occur in alcoholics, and glomeru- lonephritis is associated with hepatitis C infe ction. Although obstructive or post-renal dysfunction is not specifically associated with l iver disease, it is wise to request a renal ultrasound to exclude a hydronephrosis. 11b) What is the pathophysiology of renal dysfunction in chronic liver disease? The pathophysiological hallmark of advanced cirrhosis is systemic, par- ticularly splanchni c, vasodilatation which is caused by endogenous vasodilators (especially nitric oxide) ente ring the circulation, due to porto-systemic shunting of blood. Systemic vasodilatation is a ssociated with decreased systemic vascular resistance, which in turn leads to CASE 11 69 peripheral and splanchnic blood pooling resulting in a reduction of the effective arterial blood volume. This activates the renin-angiotensin- aldosterone system and other vasoconstr ictive neurohumoral systems, including catecholamines, in order to replenish the intravascu lar blood volume. On the one hand, this leads to sodium and water retention, while on the o ther, it induces renal vasoconstriction. Any event that fur- ther decreases renal perfusion (e.g. sepsis, gastrointestinal bleed), will cause deterioration in renal function and prec ipitate acute renal failure. 11c) What management should be instituted? Management should follow the general principles for the management of renal failure of any etiology, as well as specific measures for the liver disease. In patients with chronic live r disease, the management of acute renal failure must focus on pre-renal causes and hepator enal syndrome. Initial management comprises correction of life-threatening abnor- malities such as hyperkalaemia and hypoglycaemia. Sepsis should be treated (as in our case). The pat ient should have appropriate fluid replacement (crystalloid/colloid) to ensure that any rev ersible pre-renal component has been treated. 5% dextrose is best avoided in patients who a re hyponatraemic, but it is important to avoid sodium loading with repeated normal saline i nfusions, since this will increase total body sodium and lead to worsening of ascites. Init ial resuscitation with nor- mal saline is acceptable. The balance is difficult and volume e xpansion with albumin or other colloid and central venous pressure monitoring is appropriat e. The importance of reversing the decline of renal failure by correcting hypovolaemia cann ot be over-emphasized, because once renal failure is established it is difficult to reverse in patients with liver disease. Any gastrointestinal bleeding should be treated promptly, including vol- ume replacement. All diuretic therapy and nephrotoxic medication should be d iscontinued. If there is no improvement in the renal function after volume replacement, the diagnosis is most probably hepatorenal syndrome. There are two types of hepatorenal syndrome. Type 1 hepatorenal syndrome is rapidly progres sive, with the creatinine increasing to >250 mol/L within 2 weeks. Precipitating factors i nclude spontaneous bacterial peritonitis, major surgical procedures, and acute alcoholic he p- atitis. It follows a fulminant course, with the development of oliguria, encephalopathy, and marked hyperbilirubinaemia The prognosis is poor. Type 2 hepatorenal syndrome is chara cterized by a more benign course, with a stable reduction in glomerular filtration rate ove r weeks to OXFORD CASE HISTORIES 70 months, accompanied by diuretic-resistant ascites and avid sodium retention. Our patient ha d developed Type 1 hepatorenal syndrome. The following treatment options are potentially effective for hepatorenal syndrome: First-line therapy: vasoconstrictor drugs (e.g. bolus doses of terlipres- sin) in combinati on with albumin to expand the circulating blood volume. This improves renal function in mor e than 50% of patients. Terlipressin predominately causes splanchnic vasoconstriction, but should be used with care in patients with angina, because it can pro- voke coronary vasocon striction. Liver transplantation remains the definitive treatment, but many patients die awaiting tran splantation. Transplantation has a greater role in Type 2 hepatorenal syndrome. Artificial liver support (such as the molecular absorbent re-circulating system [MARS]), is being explored, but convincing evidence of benefit in hepatorenal syndrome is lacking. 11d) His ascites became very uncomfortable. What would you recommend? Sodium and water retention, caused by hypovolaemia and activation of the renin-angiotensin- aldosterone system in patients with cirrhosis, often leads to tense ascites, requiring larg e volume paracentesis. Paracentesis itself, however, can provoke hypovolaemia. Albumin is t herefore given during paracentesis, either as 20% or a 4.5% solution, a dose of 6 \200\2238 g of albumin per liter of ascitic fluid removed (see Case 8). The choice depends in part on availability, but also on the estimated degree of hypo- volaemia (with more concentrated a lbumin, there is a danger of exacer- bating fluid overload). This prevents deterioration of renal function and helps avoid exacerbating hepatorenal syndrome. Once a patient has estab lished hepatorenal syndrome and tense ascites, there is no evidence that draining the ascit es improves renal blood flow, so paracentesis can be left until there is an improvement in renal function unless it is causing discomfort. This patient \200\231s renal function did not improve following fluid resusci- tation and h e was treated with intravenous terlipressin 0.5mg twice daily, and 4.5% albumin infusions f or 7 days. Within 3 days his creatinine had decreased to 150 mol/L and the bilirubin to 36 mmol/L. He remains off alcohol 2 years later, with a creatinine of 78 mol/L on spironolact one 100mg/day. CASE 11 71 Further reading Betrosian AP, Agarwal B, Douzinas EE (2007). Acute renal dysfunction in liver disease. World J Gastroenterol; 13: 5552 \200\2239. Colle I, Durand F, Pessione F et al. (2002). Clinical course, predictive factors and progno sis in patients with cirrhosis and type 1 hepatorenal syndrome treated with terlipressin. A retrospective analysis. J Gastroenterol Hepatol; 17: 882 \200\2238. Fabrizi F, Dixit V, Messa P, Martin P (2009). Terlipressin for hepatorenal syndrome: A meta-analysis of randomized trials. Int J Artif Organs; 32: 133 \200\22340. Ortega R, Gines P, Uriz J et al. (2002). Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: Results of a prospective nonrandomised study. Hepatolog y; 36: 941 \200\2238. Schepke M (2007). Hepatorenal syndrome: current diagnostic and therapeutic concepts. Nephrol Dial Transplant; 22(Suppl. 8): viii2 \200\223viii4. OXFORD CASE HISTORIES 72 Case 12 A 76-year-old man from London presented with a 2-year history of diarrhea. He reported pass ing 4 \200\2237 loose, oily stools per day. He described the stool as looking like \200 \230axle grease \200\231. Over the 2-year period he had lost 4kg, but his weight had recent ly been stable. He had a history of cerebrovascular disease with dementia, ischaemic heart disease, and gout, and had had a gastroenterostomy and vagotomy in 1961 for duodenal ulcera tion. He neither smoked nor drank alcohol. Vital signs were normal. He was not pale and not jaundiced. Abdominal examination was unremarkable, apart from a scar in the midline. He had been investigated a year before for the same problem. A flexible sig- moidoscopy at the time had shown him to have diverticulosis, but biopsies of the colonic mucosa were norm al. Antiendomysial antibodies were negative. Investigations showed: 9/L, platelets 100 x 109/L, MCV 89fL mol/L, ALT 9 IU/L, ALP 169 IU/L, albumin 42g/L Hb 11.1g/dL, WCC 5.3 x 10 Bilirubin 12 CRP 4mg/L. Questions 12a) What is the clinical problem? 12b) What is the differential diagnosis? 12c) How would you investigate? 12d) What is the diagnosis in this case? 12e) How would you treat this patient? This page intentionally left blank OXFORD CASE HISTORIES 74 Answers 12a) What is the clinical problem? The description of greasy stools suggests steatorrhoea due to malabsorption. 12b) What is the differential diagnosis? The differential diagnosis includes: Intraluminal maldigestion (pancreatic insufficiency, bacterial over- growth, biliary obstru ction) Mucosal malabsorption. (Coeliac disease, Whipple \200\231s desease) Intraluminal maldigestion resulting from either exocrine pancreatic insufficiency or bacter ial overgrowth are the likely causes. Weight loss is often not prominent in these disorders and the serum albumin is usu- ally normal. Pancreatic insufficiency presenting in an elder ly patient is usually not due to alcohol-related chronic pancreatitis, which presents in th e fourth and fifth decade. Pancreatic atrophy is common in the elderly and does not itself imply exocrine pancreatic insufficiency, but some do have insufficiency without another dis cernible cause. Bacterial over- growth is common in the elderly even in the absence of anat omical abnormalities of the small bowel (see Case 10). Biliary obstruction may also cause s teatorrhoea, but this patient was not jaundiced. Mucosal malabsorption resulting from coeli ac disease is unlikely (but not totally excluded) from the negative endomysial antibody ser ology. Coeliac dis- ease only rarely causes steatorrhoea and then only in severe cases with other features, including anemia with iron and folate deficiency. Small bowel biopsies hav e not been performed in this case, so rare causes of mucosal malabsorption (such as Whipple \200\231s disease) have not been excluded, but are unlikely. A low albumin in a patient wi th steatorrhoea is usually associated with mucosal malabsorption. 12c) How would you investigate? The fecal elastase is usually diagnostic of exocrine pancreatic insuffi- ciency, but mild c ases may be missed. It is a simple, indirect measure of pancreatic exocrine function and ca n be requested on the first outpatient appointment. A concentration <200 g/g of stool is c onsistent with exo- crine pancreatic insufficiency, but in younger people the concentration should be >500 g/g. Stool water affects the measurement, so the test cannot be done on li quid stool. Fecal elastase is stable, so the test can be performed on a sample that is days old, and pancreatic enzyme supple- mentation does not affect the assay. In a population-ba sed study to CASE 12 75 quantify the prevalence of exocrine pancreatic insufficiency in people aged 50 \200\22375, 12% had a fecal elastase <200 g/L and 5% had a concentra- tion <100 g/L, so this should b e considered as a cause of unexplained weight loss. A normal fecal elastase with steatorrhoea is suggestive of bacterial overgrowth. Measuring stool fat content, however, rarely contributes to the diagnosis, and 3-day or 5-day stool f at collections are obsolete. Direct testing of exocrine pancreatic function is inconvenient and rarely used (e.g. pancreolauryl test), because of poor sensitivity. Pancreatic imaging is appropriate, if exocrine pancreatic insufficiency is confirmed. Further investigations showed: g/g Fecal elastase < 15 IgG normal CT scan of the pancreas showed an atrophic pancreas, no pancreatic mass and no ductal dilat ation (Fig. 12.1). 12d) What is the diagnosis? The patient has severe exocrine pancreatic insufficiency. Although alcohol is the most comm on cause for chronic pancreatitis, it is unlikely in an elderly patient presenting for the first time with exocrine pan- creatic insufficiency. Our patient had no pain and did not dr ink. Obstruction of the pancreatic duct by a tumor at the ampulla is an important potential cause of exocrine pancreatic insufficiency in eld- erly patients. Pancreatic insufficiency may be of unknown etiology and our patient falls into this group. Pancreatic atrophy is no t a measure of Duodenum Atrophic pancreas Aorta Fig. 12.1 A CT scan showing an atrophic pancreas. OXFORD CASE HISTORIES 76 function and may be seen in advanced age without exocrine pancreatic insufficiency. 12e) How would you treat this patient? Pancreatic enzyme replacement is appropriate. The vital constituent is lipase and the dose is determined by the lipase content. Enteric coated mini- microspheres of pancreatic enzyme s (e.g. CreonTM) are designed to release enzymes at a pH >5. Lipase is then not inactivated by gastric acid. Some patients, however, have markedly reduced pancreatic bicarbonate secr etion and benefit from the addition of a proton pump inhibitor to ensure that the pH is hig h enough for the microspheres to release the lipase in the proximal small bowel. Acid suppr ession would be inappropriate in our patient, because of the previous vagotomy. Patients ar e usually started on the equiva- lent of 25,000 units of lipase during (not after or before !) each meal, and 10,000 during snacks. The dose is adjusted according to response. Further reading Gloor B, Ahmed Z, Uhl W, Buchler MW (2002). Pancreatic disease in the elderly. Best Prac Res Clin Gastroenterol; 16: 159 \200\22370. Rothenbacher D, Low M, Hardt PD et al. (2005) Prevalence and determinants of exocrine pancr eatic insufficiency among older adults: Results of a population-based study. Scand J Gastro enterol; 40: 697 \200\223704. Domingues-Munoz JE, Iglesias-Garcia J, Iglesias-Rey M, Vilarino-Insua M (2006). Optimizing the therapy of exocrine pancreatic insufficiency by the association of a proton pump inhibitor with enteric-coated pancreatic extracts. Gut; 55: 1056 \200\2237. CASE 13 77 Case 13 A 70-year-old retired Korean mechanic presented with a 12-month history of epigastric disco mfort and 5kg weight loss. A laparoscopic cholecystectomy had been carried out for multiple gallstones. The discomfort continued post- cholecystectomy. His past medical history inclu ded a seronegative arthritis and a salivary gland biopsy consistent with Sj gren \200\231s syndrome. The patient denied drinking alcohol and was a non-smoker. He had become jaundice d over the preceding 3 weeks. On examination, the patient was jaundiced and wasted. There were no ascites or spider naevi. Investigations showed: mol/L, Na 135mmol/L, K 5.0mmol/L, urea 13mmol/L, creatinine 112 glucose 9.5mmol/L mol/L, ALT 67 IU/L, ALP 1028 IU/L Bilirubin 260 Prothrombin time: 13.0 sec Amylase 15 IU/L (normal 25 \200\223125 IU/L) Abdominal ultrasound showed a dilated bile duct and an abnormality in the pancreatic head CT scan (Fig. 13.1) ERCP: two distal common bile duct strictures and mild irregular nar- rowing of the pancreat ic duct. Brushings were negative for malignancy. Questions 13a) What are the two most likely possible diagnoses and what are the clinical and laboratory features of each? 13b) What is the main abnormality on the CT scan and how does this assist with the diagnosis? 13c) What two additional tests would help in confirming the diagnosis? 13d) What is the prognosis for the two most likely diagnoses and describe the treatment for each. OXFORD CASE HISTORIES 78 Fig. 13.1 CT scan of the abdomen in a 70-year-old man with jaundice. This page intentionally left blank OXFORD CASE HISTORIES 80 Answers 13a) What are the two most likely possible diagnoses and what are the clinical and laboratory features of each? The two principal differential diagnoses to consider are pancreatic carcinoma autoimmune pancreatitis (rare). Pancreatic carcinoma is the second most frequent gastrointestinal cancer after colorectal c ancer. Care is needed to ensure that pancreatic cancer is not assumed just because it is co mmon. Misdiagnosis is rela- tively common if only one imaging modality (such as CT scanning ) is used, and biopsy is often appropriate, especially since therapeutic use of chemotherap y depends on biopsy-proven cases. About 2% of pancreatic masses resected for suspected mali gnancy are found to be due to autoim- mune pancreatitis and these are over-represented in l ong-term survivors of Whipple \200\231s procedure for \200\230pancreatic cancer \200\231. Autoimmune pancreatitis is a benign systemic fibro-inflammatory disorder, in which the panc reas is one of several potentially affected organs. Other affected organ systems include th e bile ducts, salivary glands (note the previous diagnosis of Sj grens syndrome in this ma n), and retroperitoneal lymph nodes. Autoimmune pancreatitis can be dif- ficult to differen tiate from malignancy. Conversely, it is important not to miss the diagnosis of pancreatic carcinoma. The difficulty in diagnosis in our case is because both conditions can present with obstruc tive jaundice, a mass, and obstruction or stricturing of the bile duct. Pancreatic cancer ( affecting the head of the pancreas) generally presents with painless jaundice, with pain as a late feature. It commonly needs to be distinguished from an ampullary cancer (see Case 9 ). The principal symptom of autoimmune pancreatitis is also obstructive jaundice. Severe ab dominal pain is rare in autoimmune pan- creatitis, but most patients complain of abdominal discomfort. Recent onset diabetes is present in about half of patients with autoimmune pan- creatitis, but can also occur in pancreatic cancer. Both conditions can be associated with decreased appetite and weight loss. The concentrations of serum pancreatic enzymes are inconsistently elevated in both pancreat ic cancer and autoimmune pancreatitis, and are therefore not of any use in distinguishing b etween the two. CA19-9 is elevated in the presence of jaundice and so is not helpful in dif ferentiat- ing autoimmune pancreatitis and pancreatic carcinoma. Various patterns CASE 13 81 of elevated concentrations of serum autoantibodies have been described in patients with aut oimmune pancreatitis. These include antinuclear fac- tor, rheumatoid factor, antimitochondr ial antibody, anti-smooth muscle antibody, antibodies against carbonic anhydrate II, and la ctoferrin. Cholangiocarcinoma and primary sclerosing cholangitis may also cause distal common bile duc t strictures, but not pancreatic duct stric- tures. Chronic pancreatitis may also cause a d istal common bile duct stricture and is associated with a dilated pancreatic duct, with or without duct strictures. Nevertheless, a \200\230double duct sign \200\231 strongly sugges ts malig- nancy (see Case 9). Pancreatic calcification is common in chronic pan- creatitis, identified by CT scanning (about 60%) or plain abdominal radiograph (about 20%). There was no pancreatic calcification on the CT scan, which makes chronic pancreatitis unlikely in t his case. 13b) What is the main abnormality on the CT scan and how does this assist with the diagnosis? The characteristic appearance of autoimmune pancreatitis on CT scan is a diffusely enlarged \200\230sausage-shaped \200\231 pancreas. In autoimmune pancreatitis there is generally a sharp outline, homogenous appearance to the pancreas, and minimal or absent peripancreatic stranding. These appearances are consistent whether on CT, MRI or transabdomi- nal ultraso nography. Contrast-enhancement sometimes shows a low- contrast margin, described as a rim o r capsule on CT. Nevertheless, an appreciable number of patients with autoimmune pancreatit is do not have diffuse pancreatic involvement, but have a focal swelling or mass that mimic s pancreatic carcinoma. Dilatation, stricture, or irregularity of the main pancreatic duct, as well as the common bile duct, can occur in autoimmune pancreatitis with or without foca l swelling of the pancreatic head. Enlarged peripancreatic lymph nodes are commonly seen an d can reach a diameter of up to 30mm. A suspicion of autoimmune pancreati- tis should occur if the patient is unduly young, has coexistent autoim- mune conditions, or if there are mu ltiple strictures on the CT scan. Fortunately, the diagnosis is readily confirmed if consid ered (below). The method of choice for diagnosing and staging pancreatic cancer is also CT scanning. The pancreatic protocol for CT consists of a dual- phase scan with intravenous and oral contras t agents. The first (pancre- atic) phase is obtained 40 sec after administration of the int ravenous contrast. At this time, maximum enhancement of the normal pancreas is obtained, al lowing identification of non-enhancing (potentially neoplas- tic) lesions. The second (port al venous) phase is obtained 70 sec after OXFORD CASE HISTORIES 82 \200\230Sausage-shaped \200\231 pancreas, with a sharp outline and homogenous appearance t o the pancreas. No peri- pancreatic stranding. Fig. 13.1 CT scan of the abdomen in a 70-year-old man with jaundice. injection of the intravenous contrast, which allows accurate detection of liver metastases and assessment of tumor invasion of portal or superior mesenteric veins. 13c) What two additional tests would help in confirming the diagnosis? The two tests that distinguish between pancreatic cancer and autoim- mune pancreatitis are: Serum IgG4 concentration Pancreatic biopsy. Once considered, the diagnosis of autoimmune pancreatitis is fortunately relatively straigh tforward. An elevated IgG4 concentration (normal range 0.1 \200\2231.3g/L) has a sensitivit y of 90%, a specificity of 98% and a positive predictive value of 95% for the diagnosis of autoimmune pancreatitis. Why the inflammatory process (unlike other conditions) is so speci fic for the IgG4 is unclear. Nevertheless, pancreatic biopsy may still be required to diffe rentiate autoimmune pancreatitis from pancre- atic carcinoma. Endoscopic ultrasound examine s the pancreas in detail and allows fine-needle aspiration of lesions in the head. Although fine- needle aspiration is generally inadequate for diagnosing autoimmune pancreatitis, it has a high positive predictive value if malignant cells are found. Percutaneous pancreatic biopsy is the alternative, although it carries a 5% risk of provoking acute pancreatitis. A periductal lympho- plasmacytic infiltrate associated with fibrosis and containing >10 IgG 4- positive cells per high-power field (on immunostaining) is pathognomonic for autoimmune pancreatitis (Fig. 13.2). CASE 13 83 13d) What is the prognosis for the two most likely diagnoses and describe the treatment for each. Pancreatic cancer carries an extremely poor prognosis with less than 20% of affected patien ts surviving the first year, and only 4% alive 5 years after diagnosis. Some of these may h ave autoimmune pancreatitis in historical series. Surgical resection is the only curative t reatment, but only 15% are candidates for curative resection, because of local invasion at the time of presentation. Metastases are an absolute contraindication for resection. The st andard operation is pancreaticoduodenectomy (Whipple \200\231s procedure), which has a mort ality rate of <3% in experi- enced hands. Positive lymph nodes in the resection specimen ca rry a poor prognosis. For those patients who do not have a resectable lesion, palliation is appropriate by biliary stenting to relieve jaundice, coeliac plexus block for pain relief, surgical bypass for gastric outflow tract obstruction, or palliative chemotherapy. In contrast, autoimmune pancreatitis carries a good prognosis, which is why it is an import ant diagnosis. Until recently, diagnosis and treat- ment generally involved surgical excisi on to exclude malignancy, or because of a preoperative presumption of carcinoma. After simp le, sero- logical diagnosis (an elevated IgG4), corticosteroids are now indicated to induce complete clinical and radiological remission that is generally sustained with a return to normal serology, improvement or disappear- ance of duct stenoses, often with restoration of endocrine and exocrine function. The initial dose of prednisolone is usually 30 \200\22340 mg/day and tapered by 5mg every 2 weeks. Relapse may occur, requiring reintro- duction of c orticosteroids with immunomodulators. To avoid delay in treating malignancy, any corticoste roid-treated pancreatic mass should show near-complete resolution when reimaged 2 \200\2234 weeks after starting therapy. Any residual mass should be explored surgically. Diabetes an d pancreatic insufficiency requiring enzyme supplements may still need treatment despite co rticosteroids. This patient had autoimmune pancreatitis. He had an IgG4 of 4.0g/L (reference range 0.1 \200\2231.3g/L), and was treated with prednisolone. His jaundice resolved and CT scan retur ned to normal. Five years later he remains well with no recurrence of jaundice or weight lo ss. Further reading Kawa S, Hamano H (2007). Clinical features of autoimmune pancreatitis. J Gastroenterol; 42 (Suppl. XVIII): 9 \200\22314. OXFORD CASE HISTORIES 84 Pickartz T, Mayerle J, Lerch MM (2007). Autoimmune pancreatitis. Nature Clin Practice Gastroenterol; 4: 314 \200\22323. Sugumar A, Chari S (2009). Autoimmune pancreatitis: an update. Expert Rev Gastroenterol Hepatol; 3: 197 \200\223204. Toomey DP, Swan N, Torreggiani W, Conlon KC (2007). Autoimmune pancreatitis. Brit J Surg; 94: 1067 \200\22374. CASE 14 85 Case 14 A 68-year-old retired book keeper with alcoholic liver disease was seen in the gastroentero logy clinic with symptoms of gastro-oesophageal reflux. Thirteen years previously, she had been found to have liver cirrhosis with portal hyper- tension and oesophageal varices, whic h had bled. She had then remained absti- nent of alcohol, with improvement in her liver fun ction. She had also had a mastectomy for breast cancer 3 years before. Investigations showed: 9/L, platelets 148 x 109/L Hb 12.9g/dL, WCC 4.6 x 10 Prothrombin time 12.7 sec mol/L Na 139mmol/L, K 4.3mmol/L, creatinine 95 mol/L, ALT 19 IU/L, ALP 126 IU/L, albumin 40g/L Bilirubin 23 Ultrasound scan of the abdomen revealed a 25mm hypoechoic lesion in the right lobe of the l iver. The remainder of the liver was heterogeneous and had an irregular margin. The spleen was mildly enlarged, with a bipolar length of 13cm. CT scan of the abdomen confirmed the presence of a 33mm exophytic nodule arising from the t ip of the right lobe of the liver. This enhanced avidly in the arterial phase and was isode nse with the rest of the liver in the portal phase. There was no other focal liver lesion. The liver had a grossly irregular surface, in keeping with cirrhosis. There was splenom- eg aly (16cm), but no significant collaterals. The portal vein was patent and there were no as cites. (Figs 14.1 and 14.2). Questions 14a) What is the likely diagnosis? 14b) What are the risk factors for the development of this condition? 14c) How is this condition staged? 14d) Discuss the therapeutic options. 14e) Discuss therapy for this patient. OXFORD CASE HISTORIES 86 Cirrhotic liver Splenomegaly Fig. 14.1 CT scan showing the cirrhotic liver. Note the shrunken liver with irregular outli ne and enlarged spleen, due to portal hypertension. Enhancing nodule Renal enhancement in the arterial phase Fig. 14.2 A CT scan showing a round lesion at the tip of the right lobe of the liver, with intense contrast enhancement seen during the arterial phase. This page intentionally left blank OXFORD CASE HISTORIES 88 Answers 14a) What is the likely diagnosis? An isolated space-occupying lesion in a cirrhotic liver is highly suspi- cious of hepatocel lular carcinoma. In this case, the lesion was >2cm in diameter and hypervascular, shown by contrast enhancement in the arterial phase of the CT scan, which is characteristic of hepat ocellular carcinoma. The diagnosis of hepatocellular carcinoma is probable in a cirrhotic liver when two radiolo gical modalities show a focal lesion, with contrast enhancement in at least one imaging tec hnique. A lesion seen on a single imaging modality with contrast enhancement plus serum - fetoprotein >400ng/ml is also considered diagnostic. A false-positive elevation in -fetop rotein may occur in chronic viral hepatitis with active replication and no focal liver lesi on, or acute hepatic necrosis from any cause. Furthermore, the serum -fetoprotein may be within the normal range if the hepatocellular carcinoma is <2cm in diameter. Preoperative s equential radiological imaging is 98% sensitive and 100% specific for predicting hepatocell ular carcinoma by these criteria. Needle biopsy of a liver lesion suspected of being a hepa tocellular carcinoma is best avoided, because there is a 1.5 \200\2235% risk of tumor seedi ng in the needle tract. Biopsy, however, is reasonable in lesions of >2cm if radiological f indings are indeterminate, or if the tumor is unresectable, and a decision on systemic ther apy depends on the histopathology. The characterization of liver lesions <2cm in diameter, remains diffi- cult. Lesions <1cm s till carry a 50% chance of being malignant. Consequently interval ultrasound scanning (abou t 3-monthly) is recom- mended to identify enlargement. For lesions 1 \200\2232cm in diamete r, biopsy may well be appropriate, but should be discussed with the hepatobiliary surgeon w ho will potentially resect the lesion. Small tumors may be well differentiated and difficul t to distinguish histologically from normal liver. Fluorescent in situ hybridization (FISH) analysis, which is already used in the diagnosis of cholangiocarcinoma from cytological sa mpling of biliary strictures, may help by demonstrating aneuploidy in suspicious liver lesi ons. Aneuploidy is diagnostic of neoplastic transformation. 14b) What are the risk factors for the development of this condition? Liver cirrhosis of any cause is the main risk factor for the development of hepatocellular carcinoma, since 80% develop in cirrhotic livers. Hepatitis C virus infection accounts for most cases in the developed CASE 14 89 world and up to a third will develop hepatocellular carcinoma in their lifetime. The annual incidence is 3 \200\2235% in this group. In Asia and Africa, chronic hepatitis B virus inf ection is the major cause, with an annual incidence of 2 \200\2236% in those with cirrhosis . Consequently, screening for hepatocellular carcinoma is recommended for patients with cir rhosis, usually by ultrasound of the liver at 6-monthly intervals. Even though the sensitiv ity of ultrasound is low (20 \200\22350%), specificity is 92 \200\22396% in cirrhotic patie nts and it is readily available, relatively low cost, and carries no risk. Sensitivity is l east for small lesions. Magnetic resonance imaging with angiography has a high sensitivity for lesions 1 \200\2232c m in diameter, but is expensive, insensitive for lesions <1cm, and not uniformly available. It is (with CT) used mainly to con- firm a diagnosis of hepatocellular carcinoma when ultr asound has detected a liver lesion. Positron emission tomography has low sensitivity for le sions <2cm in diameter. Nevertheless, there are no data that show a survival benefit from s creening in cirrhosis, although patients who have a hepatocellular carcinoma detected in th e context of a screening pro- gramme have smaller tumors with a higher application of poten tially curative therapies. 14c) How is this condition staged? Staging of hepatocellular carcinoma is complicated, because the severity of the underlying liver disease affects survival, as well as the tumor-related stage. The Barcelona-Clinic Li ver Cancer stage takes into account tumor characteristics (size, vascular invasion, and ext ra-hepatic spread), stage of liver disease (Child \200\223Pugh score, portal hypertension, bilirubin), and the patient \200\231s performance status. This is currently the standard fo r manage- ment of hepatocellular carcinoma. Patients with hepatocellular carcinoma are divi ded into three groups, Stage 0, Stages A \200\223C, and stage D: Stage 0 (very early stage): Child \200\223Pugh A, performance status 0 with carcinoma in si tu or a single mass <2cm Stages A \200\223C (early stage [A], intermediate stage [B], and advanced stage [C]): all C hild \200\223Pugh A or B Stage A: single to 3 nodules <3cm and performance status 0 Stage B: multiple nodules and performance status 0 Stage C: portal invasion, lymph node or distant metastases, and performance status 1 \200 \2232 Stage D (Terminal stage): Child \200\223Pugh C, performance status 3 \200\2234 with extensi ve liver involvement (accounts for >50% of patients). OXFORD CASE HISTORIES 90 14d) Discuss the therapeutic options Therapeutic options depend on the stage and can be divided into resect- able or unresectabl e disease. Only stage 0 and stage A tumors are potentially resectable and only these are po tentially curable. Stage A hepatocellular carcinoma has a 5-year survival of 50 \200\22370% if treated by orthotopic liver transplantation, resection, or complete local ablation. Eve n in this group, outcomes vary. Three subgroups (defined as a single tumor of <2cm, a singl e tumor 2 \200\2235cm and, up to three lesions with none larger than 3cm in diameter) each have different treatment out- comes. Orthotopic liver transplantation can be considered if there is a single tumor <5cm, or up to three lesions with none larger than 3cm (the so-call ed Milan criteria). Transplantation has the potential advan- tage of curing the underlying liver disease and removing the risk of subsequent tumors, and a 5-year survival of 70% has been reported.