This page intentionally left blank OXFORD CASE HISTORIES 48 Answers 8a) Describe the clinical problem at presentation to the clinic. How would you assess the s everity and what would be your initial management? This patient presents with decompensated chronic liver disease. There is likely to be cirrh osis, owing to stigmata of chronic liver disease, a low platelet count, and a long history of inadequately treated Wilson s disease. Ascites indicates portal hypertension complicatin g chronic liver disease, but does not always indicate cirrhosis. The absence of a clear pre cipitant (e.g. gastrointestinal bleed, infection, or acute toxic liver insult), suggests th at the decompensation results from progression of the underlying liver disease alone. Assessment of severity The degree of liver dysfunction in cirrhosis is graded using the Child \200\223 Pugh classi fication. This classification scores the serum levels of bilirubin, albumin, and prothrombi n time, and the presence/severity of ascites and encephalopathy. The total score ranges fro m 5 to 15 and places a patient in one of three groups that reflect increasing severity of d isease (Table 8.1). The groups (and corresponding scores) are: Child \200\223Pugh A (5 \200\2236), B (7 \200 \2239) and C (10 \200\22315). There are several limitations to the score. The five variable s were selected empirically and not based on statistical regression; cut-off values are arb itrary; and each variable is given the same weight. Renal function, which is an important p rognostic variable, is not taken into account. However, it is user friendly and has stood t he test of time, because it relates to outcome. Survival at 5 years and 10 years in cirrhot ic patients are 95% and 90%, respectively in Child A, 75% and 60% in Child B, and 55% and 3 0% in Child C. Another score, the Model for Endstage Liver Disease (MELD), was initially devised to predic t prognosis in patients being considered for Table 8.1 Child \200\223Pugh Score Measure 1 point 2 points 3 points units Bilirubin <34 (<2) 34 \200\22350(2 \200\2233) >50 (>3) mol/L (mg/dL) Albumin >35 28 \200\22335 <28 g/L INR <1.7 1.71 \200\2232.20 >2.20 N/A Ascites None Diuretic responsive Refractory N/A Encephalopathy None Gr I-II Gr III-IV N/A CASE 8 49 transjugular intrahepatic portal systemic shunts (TIPSS). It is derived from statistical re gression analysis, with each variable given the appropri- ate weight, and it includes renal function. It requires a calculator, is not user friendly at the bedside, but is used in th e USA for patients being considered for transplantation. Model for Endstage Liver Disease: 9.6 loge(creatinine in mg/dL) + 3.8 loge (bilirubin in mg/dL) + 11.2 loge (INR) + 6.4 Calcu lator: www.unos.org/resources/meldpeldcalculator.asp Interpretation of score (predicted 3-m onth mortality): 40 or more: 100% mortality 30 \200\22339: 83% mortality 20 \200\22329: 76% mortality 10 \200\22319: 27% mortality <10: 4% mortality. This patient was Child \200\223Pugh B (score 9) at presentation, with a MELD score of 15. Management Management at this stage would be aimed at control of fluid retention, which is the main re ason that the patient was referred. His ascites had already improved on spironolactone, whi ch had been prescribed by the family practitioner. Therapeutic drainage of the ascites was not indicated at this stage. Spironolactone has a long half-life and should be given at a o nce daily dose of 100 \200\223400mg/day. It is an aldosterone antagonist, which promotes re nal sodium loss and conserves potassium. Dose adjustments should consider the serum potassi um, because hyperkalaemia is a major adverse effect. It is antiandrogenic and may lead to g ynaecomastia. Fluid restriction is not required at this stage, but salt (NaCl) restriction is advis- able. Sodium intake should be restricted to 90mmol/day (5.2g of salt/day), which can be achieved by a \200\230no-added-salt \200\231 dictum and avoiding pre-pre- pared or canned food. The patient does not yet have neurological signs of Wilson s disease, so penicillamine shou ld initially be continued at a dose of 500mg twice a day, in the hope that liver function w ill improve. Adherence to therapy is a complex topic and should be addressed empathetically , with appropriate support to ensure that medication is taken. OXFORD CASE HISTORIES 50 Complete abstinence from alcohol is also advisable, even though his previous intake was low . Percutaneous liver biopsy is too risky at this stage, in view of the pressure of ascites and the prothrombin time which is already prolonged and would not alter management. It is i mportant, nev- ertheless, to exclude concomitant liver disease, and a full liver screen sho uld be performed (see Case 1), to exclude viral hepatitis in view of the travel history. An ultrasound scan of the abdomen should be requested to document liver size, exclude hepatoc ellular carcinoma (which is rare in Wilson \200\231s disease) or portal vein thrombosis, an d to document spleen size. An endoscopy would be appropriate to look for varices. 8b) What precipitated the deterioration that led to the hospital admission? The acute deterioration resulted from spontaneous bacterial peritonitis. Five weeks after h is initial clinic appointment the patient presented with marked deterioration of his condit ion, with tense ascites, rising bilirubin, further prolongation of prothrombin time and a d ecline in serum albu- min. He had a systemic inflammatory response (tachycardia, fever, and elevated WCC), but no encephalopathy or evidence of gastrointestinal hemorrhage. Bacterial infection is by far the most likely cause. The following should be carried out: blood cultures diagnostic paracentesis, with ascitic fluid analysis for albumin, cell count, and culture. Spontaneous bacterial peritonitis is diagnosed when the ascitic fluid polymorphonuclear leu cocyte count exceeds 250/mm3 of fluid. In this patient the cell count was marginal (254/mm3 of fluid), but diagnostic in the circumstances. The Gram stain was negative, which is typi cal in spon- taneous bacterial peritonitis, because there is a low bacterial load. Fluid cu lture was also negative, which is also typical, because it depends on the method used. Cult ures are positive in 40% (fluid sent in a sterile container for inoculation onto culture me dium) to 80% (inoculation into blood culture medium at the bedside). An obsolete term \200 \230culture-negative neu- trocytic ascites \200\231 is now thought to represent the 20 \200 \22360% of patients who have spontaneous bacterial peritonitis and a false-negative ascitic fluid culture. The very low ascitic fluid albumin concentration, resulting in a high serum -ascites albumin gradient (>11g/L), indicates portal hyper- tension as the cause of the asc ites. Low protein concentration in the ascitic fluid is a risk factor for spontaneous bacte rial peritonitis. Secondary bacte- rial peritonitis should be suspected if a polymicrobial infection is detected on culture. CASE 8 51 8c) What treatment would you give? Intravenous third generation cephalosporin antibiotics or oral quinolones are the mainstay of therapy. The most common bacterial isolates are Escherichia coli, Klebsiella sp., entero cocci, and streptococci. Antibiotics given for 5 days seem to be as effective as 10 days, s o the shorter course should be given. Oral fluoroquinolones are an alternative to intraveno us cefotaxime in patients who are not encephalopathic or vomiting. Aminoglycoside antibioti cs are best avoided in patients with decompen- sated liver disease, because of an unpredict able volume of distribution (ascites) and the risk of precipitating renal failure. Antibiot ic therapy should be started as soon as the ascitic polymorphonuclear leucocyte count confi rms the diagnosis, so an urgent request for analysis is appropriate. Patients with spontaneous bacterial peritonitis are at risk of hepatorenal syndrome (see Ca se 11), due to bacterial translocation triggering inflam- matory pathways in patients with intravascular hypovolaemia. To reduce the risk, volume expansion with albumin is appropriat e. A 19% absolute risk reduction in mortality (from 29% to 10%) has been reported when albu min is given. When albumin infusion is compared with another col- loid, albumin appears to be superior in maintaining circulatory function, although studies have been underpowered to show a reduction in renal failure or mortality. Albumin should be given at a dose of 1.5g/ kg on day 1, followed by 1g/kg on day 3 to patients with an increased or rising serum creat inine. 8d) Describe whether and how you would perform a therapeutic paracentesis In view of the tense ascites, \200\230total \200\231 paracentesis (until no further fluid can be drained) is best performed. This removes a large volume of ascitic fluid (>5L), whic h can potentially cause circulatory dysfunction, renal impair- ment, and hyponatraemia. Asc ites can, however, be removed rapidly as long as it is combined with the administration of 6 \200\2238g albumin for every liter of fluid removed. The drainage catheter should be remo ved as soon as possible, ideally within 6 hours, in order to minimize secondary infection. 8e) How should this patient be managed in the future? Management of ascites and hyponatraemia Management includes fluid restriction to less than 1.5L/day and \200\230no-added salt \200 \231 dictum. Spironolactone is continued unless hyponatraemia gets worse or the urea rises, in which case it should be reduced or stopped. A loop diuretic (e.g. frusemide (at a start ing dose of 20mg/day)) may be added OXFORD CASE HISTORIES 52 once spironolactone has been given at a maximum dose (400mg/day) for 5 days, if ascites rea ccumulates, but particular caution is necessary to avoid exacerbating hyponatraemia and ren al impairment. Further paracentesis may be needed. Prevention of further spontaneous bacterial peritonitis Patients who develop spontaneous bacterial peritonitis have a mortality in the following 12 months of 20 \200\22340% after their first episode and 40 \200\22370% after a second episo de. Secondary antibiotic prophylaxis with cipro- floxacin 500mg/day or norfloxacin 400mg/da y reduces infection and mortality. In one study prophylactic antibiotics reduced recurrent sponta- neous bacterial peritonitis from 68% to 20%, and Gram-negative infec- tion to 3%, a lthough it may increase in Gram-positive infections including MRSA. Orthotropic liver transplantation Referral for orthotropic liver transplantation (OLT) should be considered (see Case 1 and C ase 47). Further reading Moore KP, Aithal GP (2006). Guidelines on the management of ascites in cirrhosis. Gut; 55(Suppl. VI): VI1 \200\223VI12. Durand F, Valla D (2005). Assessment of the prognosis of cirrhosis: Child \200\223Pugh vers us MELD. J Hepatol; 42: S100 \200\223S107. Koulaouzides A, Bhat S, Karagiannidis A, Tan WC, Linaker BD (2007). Spontaneous bacterial peritonitis. Postgrad Med J; 83: 379 \200\22383. Sort P, Navasa M, Arroyo V et al. (1999). Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Eng J Me d; 341: 403 \200\2239. Neuberger J, Gimson A, Davies M et al. (2008). Selection of patients for liver transplantat ion and allocation of donated livers in the UK. Gut; 57: 252 \200\2237. CASE 9 53 Case 9 A 59-year-old man presented with a 4-week history of jaundice, 6kg weight loss, pale stools , and dark urine. He had not experienced any abdominal pain. There was no previous medical history and he was not taking any regular medication. Alcohol intake was 25 standard drinks per week and the patient smoked 40 cigarettes/day. On examination, he was afebrile, jaundiced, and the liver edge was palpable 2cm below the c ostal margin. There were no stigmata of chronic liver disease. Investigations showed: 9/L, platelets 124 x 109/L Hb 13.5g/dL, WCC 4.5 x 10 mol/L Na 134mmol/L, K 3.7mmol/L, urea 4.1mmol/L, creatinine 100 mol/L, ALT 120 IU/L, ALP 1506 IU/L, albumin 36g/L Bilirubin 240 Prothrombin time 19 sec Abdominal ultrasound: dilated common bile duct (12mm), with mildly dilated intrahepatic duc ts, no stones in the gallbladder. Pancreas not seen ERCP is shown in Figs 9.1a and 9.1b CT scan of the abdomen is shown in Fig. 9.2. Questions 9a) What investigations need to be done prior to ERCP? What does the ERCP show (Figs 9.1a and 9.1b)? 9b) What does the CT show (Fig. 9.2)? 9c) Give a differential diagnosis. 9d) How would you treat this patient and what is the prognosis? OXFORD CASE HISTORIES 54 Fig. 9.1a and 9.1b CASE 9 55 Fig. 9.2 OXFORD CASE HISTORIES 56 Answers 9a) What investigations need to be done prior to ERCP? What does the ERCP show (Figs 9.1a and 9.1b)? Correct INR If a sphincterotomy or pre-cut is being considered, then the prothrombin time should be cor rected prior to the procedure. In biliary obstruction the prothrombin time corrects rapidly with vitamin K (unlike in chronic liver disease), which is best given the day before the p rocedure. If a biliary stent is being inserted without sphincterotomy, then an INR of \211 2 is acceptable. Magnetic resonance cholangiography This is a non-invasive approach to imaging an obstructed biliary system. Current protocols consider this a necessary investigation before ERCP; the investigation is debatable in a ja undiced patient such as this, with objective evidence on ultrasound of biliary obstruction, but much depends on local availability of MR scanning and access to ERCP. Prophylactic antibiotics Ascending cholangitis results from bacterial infection of an obstructed biliary system, usu ally from enteric Gram-negative microorganisms, resulting in bacteraemia. There is incomple te drainage of the biliary sys- tem after ERCP in up to 10% of patients after stenting. Ant ibiotics started in these patients may reduce the frequency of cholangitis by 80%. If anti- biotics are restricted to this group, \211\21090% of all patients having an ERCP will avo id antibiotics, but 80% of cholangitic episodes will be prevented. The British Society of G astroenterology Guidelines suggest the follow- ing prophylaxis: Oral ciprofloxacin 750mg 60 \200\22390 min before procedure OR gentamicin 120mg intravenously just before the procedure OR intravenously, just before the procedure. a parenteral quinolone, cephalosporin or ureidopenicillin, given Explain risks of ERCP to the patient Complications of ERCP occur in 5 \200\22310% of patients. The precise risk depends on the p articular patient, disease, and type of procedure. Pancreatitis is the most common complica tion of ERCP; it occurs in 3 \200\2235%. Pancreatitis usually resolves in 1 \200\2233 days, but severe pancreatitis occurs in about 1% of ERCP procedures. Severe pancreatic damage ca n CASE 9 57 result in the formation of a pseudocyst or abscess, which may require a prolonged stay in h ospital. Rare fatal cases of pancreatitis related to ERCP have been reported. Other complic ations are less common and occur mainly after intervention such as sphincterotomy. This inc ludes bleeding, which may necessitate a blood transfusion or surgery. Sphincterotomy can al so result in perforation when the cut extends into the tissues behind the duodenum and panc reas. Some perforations can be treated medically (with intravenous fluids, antibiotics and a nasogastric tube); other cases may require surgery and prolonged hospital treatment. Very rarely, the endoscope itself can perforate the esophagus, stomach, or duodenum. This type of perforation usually requires surgery. Images The ERCP (Fig. 9.1a) shows a dilated common bile duct and pancreatic duct (double duct sign , highly suggestive of an obstructing carcinoma), and a dilated intrahepatic biliary tree. Fig. 9.1b shows the biliary stent in situ and a dilated pancreatic duct. 9b) What does the CT show? It is important that the CT scan is performed prior to the ERCP, because stent insertion or post-ERCP pancreatitis makes interpretation of the ERCP scope Dilated common bile duct Dilated pancreatic duct (a) Persistent dilation of the pancreatic duct Stent in the common bile duct (b) Fig. 9.1a and 9.1b OXFORD CASE HISTORIES 58 CT scan very difficult. It is for this reason that current protocols also rec- ommend magne tic resonance cholangiopancreatography prior to ERCP. The CT (Fig. 9.2) shows a dilated pan creatic duct. This determines that the level of biliary obstruction is low. There is no vis ible lesion in the head of the pancreas, no evidence of lymphadenopathy, or metastatic dise ase. 9c) Give a differential diagnosis: Ampullary tumor Carcinoma of the head of the pancreas Bile duct stones Cholangiocarcinoma Benign bile duct stenosis. See Fig. 9.3 for an investigation algorithm. The two most common causes of the \200\230double duct sign \200\231 (simultanous dilatatio n of both the pancreatic and bile ducts) are carcinoma of the head of the pancreas and carc inoma of the ampulla of Vater. Both conditions present with obstructive jaundice and weight loss. The endoscopic photo- graph of the ampulla (Fig. 9.4 in central color section) makes it very likely that this is an ampullary carcinoma. Cholelithiasis with impaction of a gal lstone in the ampullary area could cause simultanous dilatation of the pancreatic and bile duct; however, this would generally be accompa- nied by biliary colic and not associated wi th weight loss. It is uncommon for a cholangiocarcinoma to cause a double duct sign, and be nign bile Fig. 9.2 CASE 9 59 DILATED COMMON BILE DUCT (identified on abdominal CT or ultrasound, often incidental) MRCP to look at pancreatic duct If pancreatic duct normal Asymptomatic Normal LFT No further Investigations RUQ pain and/or weight loss but normal LFTs CT: If no mass on CT or MRCP, use side viewing endoscope to examine papilla. If normal watc h and rescan in 3 \200\2236 months. If a mass is visible and a surgical candidate, then end oscopic ultrasound (EUS) before Whipple \200\231s or local resection RUQ pain and/or weight loss and abnormal LFTs ERCP If pancreatic duct dilated (remember that a mildly dilated duct is common in the elderly) Suggestive of ampullary tumor: endoscopy with side-viewing endoscope and ampullary biopsies If normal ampulla at endoscopy proceed as below: Asymptomatic + normal LFT CT: If CT and MRCP normal, then repeat in 3 months. Then, if pancreatic duct is more dilate d, perform EUS if a candidate for surgery. Otherwise no further investigation endoscopic ultrasound (EUS) if a candidate for for surgery RUQ pain and or weight loss + normal LFTs RUQ pain and/or weight loss + abnormal LFTs ERCP * abnormal LFT = elevated alkaline phosphatase (assuming no other cause) Fig. 9.3 Algorithm for managing patients with biliary obstruction duct stenosis generally follows iatrogenic injury; there was no previous surgery in this ca se. 9d) How would you treat this patient and what is the prognosis? Pancreatoduodenectomy (Whipple \200\231s procedure) is the treatment of choice for patients with an ampullary carcinoma. Resectability rates approach 90%, compared with 25% in pancre atic adenocarcinoma. The explana- tion for the greater resectability rate for ampullary ade nocarcinoma is multifactorial. It can partly be explained by earlier presentation (because the anatomic location of the tumor provokes jaundice at an early stage), but may also refle ct a different biological behavior compared with pancreatic cancer. OXFORD CASE HISTORIES 60 Fig. 9.4 (see color plate 4) Endoscopic photograph of the tumor (large arrow) after stent ( small arrow) insertion Nodal metastases are present at diagnosis of ampullary carcinoma in 35% (usually adjacent p eriampullary nodes). Overall 5-year survival after resection is 40 \200\22350%, but this in creases to 80% if there are no nodal metas- tases. This is much better than pancreatic or c holangiocarcinoma, which have 5-year survival rates of 10 \200\22320%, so it is important t o make the dis- tinction. Poor prognostic factors include advanced stage, tumor size >2.5cm , perineural invasion, angiolymphatic invasion, nodal metastases, signet-ring or poorly dif ferentiated histopathology, and positive (R1) resection margins. Patients with ampullary adenocarcinoma can benefit from 5-fluorour- acil (5FU)-based chemor adiotherapy after resection, especially node posi- tive (N1) patients. If metastatic or unr esectable local disease is found at the time of surgery, palliation with a Roux-en-Y hepati cojejunostomy bypass is appropriate. In this patient, the tumor was resected and histology showed a moder- ately differentiated ampullary adenocarcinoma, with 11/25 nodes posi- tive. Neo-adjuvant chemotherapy with weekl y 5FU was given after surgery. The patient remains well 3 years later. Further reading Clarke DL, Pillay Y, Anderson F, Thomson SR (2006). The current standard of care in the per iprocedural management of the patient with obstructive jaundice. Ann R Coll Surg Engl; 88: 610 \200\22316. Coss A, Enns R (2009). The investigation of unexplained biliary dilatation. Curr Gastroenterol Rep; 11: 155 \200\2239. Dittrick GW, Mallat DB, Lamont JP (2006). Management of ampullary lesions. Curr Treat Options Gastroenterol; 9: 371 \200\2236. Tran TC, Vitale GC (2004). Ampullary tumors: endoscopic versus operative management. Surg Innov; 11: 255 \200\22363. CASE 10 61 Case 10 A 78-year-old woman from Yorkshire was referred with a 5-year history of diarrhea that was predominantly nocturnal. Symptoms had worsened over the preceding 12 months. She would have to get up three or four times to open her bowels, on 3 or 4 nights a week. Daytime frequen cy was only twice, but stools were often explosive, pale and sometimes left a residue after flushing. She had lost 10kg in 2 years, but her appetite was normal. She had been referred 2 years previously and been investigated. A barium enema had shown sigmoid diverticular di sease, but no other abnormality. A macrocytic anemia (Hb 10.8g/dL, MCV of 132fL) had been f ound, attributable to vitamin B12 defi- ciency. Her folate was normal, towards the upper li mit of the range. Vitamin B12 replacement every 3 months had been started. On examination, she was cachectic and weighed 51kg. Investigations showed: 9/L, platelets 224 x 109/L, MCV 98fL Hb 12.7g/dL, WCC 8.0 x 10 CRP 9mg/L U&E normal Albumin 31g/L g/g (normal >200 g/g) Fecal elastase 248 Endomysial antibody serology negative. A small bowel enema was requested and the patient was started on empirical treatment. Questions 10a) What is the differential diagnosis? 10b) Name three conditions that predispose to the most likely diagnosis. 10c) How is the diagnosis made? 10d) How would you manage this patient? 10e) Discuss the underlying condition. OXFORD CASE HISTORIES 62 Answers 10a) What is the differential diagnosis? Small intestinal bacterial overgrowth results from an excess of bacteria in the small bowel , often associated with abnormal small bowel anatomy and/or motility. It characteristically causes painless, explosive and malo- dorous diarrhea, weight loss, and B12 deficiency. Bac teria deconjugate bile acids and prevent effective emulsification of dietary fat, with subs e- quent steatorrhoea. Anaerobic organisms metabolize dietary vitamin B12 into inactive cob amides. These cobamides then compete with ileal binding sites for vitamin B12 absorption, l imit absorptive capacity, and eventually lead to deficiency. In contrast, folic acid absorp tion is unaf- fected and bacterial production of folate may lead to high folic acid concent rations. Reduced disaccharidase activity in the brush border, secondary to small intestinal bacterial overgrowth, causes lactose intoler- ance, which contributes to the diarrhea. Exocrine pancreatic insufficiency is also characterized by steator- rhoea (see Case 12) and may cause vitamin B12 deficiency, because pan- creatic enzymes are needed to release vitam in B12 from R-binding protein. R-binder combines with vitamin B12 in the stomach to protect it from degradation when exposed to gastric acid. In our patient, how- ever, the fecal ela stase concentration was normal (>200 g/g), which makes pancreatic insufficiency unlikely. In younger people, a fecal elastase of 200 \200\223500 g/g still raises the possibility of exocrine pancreatic insufficiency. Small bowel mucosal pathology (such as coeliac or Whipple \200\231s disease) may cause stea torrhoea and occasionally vitamin B12 deficiency. Coeliac disease with negative endomysial antibody serology is very unusual (<5% in most published series, although may be slightly m ore common in practice). Nocturnal diarrhea should always be considered to have an organic cause and not attributed to a functional bowel disorder (such as irritable bowel syndrome) until proven otherwise. O ther conditions that cause chronic nocturnal diarrhea (such as microscopic colitis) do not cause B12 deficiency. Any condition resulting in B12 deficiency needs to have been present for years, because the physiological daily requirement for vitamin B12 is about one thousan dth of total body stores. In this woman, the most likely cause was small intestinal bacteri al overgrowth. A small bowel enema was requested to define small bowel anatomy and extensive jejunal diverticulosis was identified (Fig. 10.1). CASE 10 63 Tube for performing enterococlysis Normal small bowel Diverticulum Fig. 10.1 A small bowel enema showing multiple jejunal diverticula. 10b) Name three conditions that predispose to the most likely diagnosis Small intestinal bacterial overgrowth is typically associated with ana- tomical abnormaliti es of the small bowel, either spontaneous or acquired after surgery, and from conditions th at affect small bowel motility. Stasis of luminal fluid promotes bacterial growth. Small in testinal resection and anastomosis may create a blind loop, while resection of the ileocae- cal valve promotes retrograde flow of colonic contents and bacteria into the small bowel. The most common postoperative association with small intestinal bacterial overgrowth is ile ocolic resection for Crohn \200\231s disease, but in the past partial gastrectomy with a Bi lroth II or Roux-en-Y anas- tomosis were often complicated by a \200\230blind loop syndrom e \200\231 that include diarrhea due to bacterial overgrowth. Acquired conditions include small bowel strictures and small bowel diverticulosis. Strictur es are commonly caused by Crohn \200\231s disease, but radiation enteropathy and non-steroi dal drugs may also cause strictures and upstream stasis. Small bowel dysmotility in systemi c sclerosis and autonomic neuropathy (most commonly complicating diabetes) may cause small intestinal bacterial overgrowth. Nevertheless, small intestinal bacterial overgrowth may oc cur with normal intestinal anatomy, includ- ing achlorhydria and old age. It is conceivable that proton-pump inhibi- tors in the elderly may predispose to small intestinal bacterial overgrowth. Old age may be associated with small intestinal bacterial overgrowth due to mul tiple factors including reduced intestinal motility, reduced IgA secretion, small bowel div erticulosis, which is more common in old age, OXFORD CASE HISTORIES 64 previous intestinal surgery, and achlorhydria. Small intestinal bacterial overgrowth should be considered in patients with coeliac disease whose symptoms persist despite avoiding die tary gluten, and in patients with rheumatoid arthritis, who may have small intestinal bacte rial overgrowth associated with disease activity. 10c) How is the diagnosis made? Small intestinal bacterial overgrowth is an epiphenomenon associated with other gastrointes tinal conditions. The diagnosis is often clinical, since the explosive, malodorous, painles s diarrhea with or without weight loss is characteristic in a patient with a predisposing c ondition. A low B12 and high folate are characteristic, but relatively uncommon in practice . Bacterial concentration and composition changes from the proximal to the distal small intes tine: the number of colony forming units (cfu)/mL increase and the composition changes from predominantly Gram-positive bacteria to Gram-negative and anaerobic bacteria. Colonization of the proximal small bowel with coliforms and anaerobes is abnormal and may cause symptom s at lower concentrations than Gram-positive bacteria. Culture of small bowel aspirate is the gold standard for diagnosis of small intestinal bact erial overgrowth (generally defined as more than 105 cfu/mL), but rarely employed. The thre shold of 105 cfu/mL is based on early studies of patients with surgically constructed blind loops. Nevertheless, small bowel culture is difficult and invasive, because it requires an aspirate that may itself become contaminated. Non-invasive tests are far more attractive. A variety of breath-tests exist, based on the a bility of bacteria to produce hydrogen (H2) or car- bon dioxide (CO2), through the metaboli sm of specific carbohydrate substrates that may be radio-labeled. These include glucose, la ctulose and d-xylose. If glucose or lactulose are used, H2 is measured in the breath. Bacte ria are the only producers of hydrogen in the intestine and detection of >20ppm within 2 ho urs of ingestion implies bacterial production from the small intestine. However, 15 \200 \22320% of patients produce methane or hydrogen sulfide, which are undetectable by con- ven tional hydrogen analysers and may give rise to false-negative results. Glucose is almost en tirely absorbed in the first meter of small intestine, so a positive test implies proximal small intestinal bacterial overgrowth. Lactulose, however, is not absorbed at all, but is subsequently fermented in the colon, giving a late peak (>2 hours) in breath hydrogen, whic h is normal. An early peak (<2 hours) is considered positive, but the test is difficult or impossible to interpret in patients with rapid intestinal transit CASE 10 65 or after small bowel resection. The glucose hydrogen breath test, when compared with cultur e of small bowel aspirate, has a sensitivity of 27 \200\22358% and specificity of 30 \200 \22383%. The lactulose hydrogen breath test has a sensitivity of 17 \200\22389% and a speci ficity of 44 \200\223100%, so the latter is generally preferred. In contrast to hydrogen, 1 3C-d-xylose or 14C-d-xylose administration enables the measurement of 13CO2 or 14CO2 in the breath. The 14C-D-xylose breath test has a sensitivity of 40 \200\223100% and a specificit y of 40 \200\223100%, but the use of a radioisotope is a drawback. Formal assessment of small intestinal bacterial overgrowth is therefore fraught with diffic ulty, because there is not only heterogeneity in studies comparing non-invasive tests to ba cterial culture, but the gold standard is itself also of questionable validity. A systemati c review has questioned the validity of current non-invasive breath tests based on an inade quate gold standard. Correlation in studies is recommended between a com- patible clinical syndrome, non-invasive tests, and an appropriate response to therapy. In clinical practice it is reasonable to give empirical antibiotic therapy to a patient with compatible symptoms and a predis- posing cause. This is simple and usually sufficient. 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?