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. For patients who have resectable disease but are not considered suitable for transplant, he patic resection depends on the stage of liver disease. The best candidates for resection ar e patients with cirrhosis who are Child \200\223Pugh A, have a normal bilirubin, and no cli nical evidence of por- tal hypertension. Only 10% of patients fall into this category. Hepa tocellular carcinoma without cirrhosis is uncommon in the west (5%), but much more common i n Asia (40%). Resection is the therapy of choice. Within this group, outcomes are worse for larger tumors, since size is a surrogate marker for vascular invasion. Local ablation is potentially appropriate for patients with Stage A hepatocellular carcinom a who are unsuitable for resection or transplan- tation. Eighty percent of tumors <3cm can be completely ablated, but only 50% of tumors 3 \200\2235cm in diameter. Five-year survival is 40 \200\22370%. Patients who are Child \200\223Pugh A, with single, small tumors (<3cm) fare best. Techniques include percutaneous ethanol injection and radiofre- quency ablation . Radiofrequency ablation is more effective than ethanol, but there are no data comparing o utcomes between ablation and resection. Patients who have unresectable disease have a media n survival <1 year, although heterogeneity is illustrated by the fact that 2-year survival ranges from 8% to 50%. Intermediate (stage B) hepatocellular carcinoma is defined as an unre- sectable tumor in an asymptomatic patient and carries a median sur- vival of 16 months. This can be extended to 20 months by hepatic artery chemoembolization in those patients with a patent portal vein. CASE 14 91 Advanced (stage C) hepatocellular carcinoma (symptomatic patients with extrahepatic spread or vascular invasion) have a median survival of 6 months. Sorafenib, a multi-kinase inhibit or, has been shown to improve survival in these patients by a median of 3 months, becoming the first systemic therapy for hepatocellular carcinoma to show a clini- cally significant benefit. It stabilizes disease, as opposed to inducing tumor shrinkage, which is the tradit ional measure of response to cyto- toxic chemotherapy. End-stage hepatocellular carcinoma (Stage 0, performance status 3 \200\2234, severe tumor r elated symptoms), or patients with Child \200\223Pugh C cir- rhosis have a dismal prognosis , with a median survival of 3 months. Palliative care is appropriate. 14e) Discuss therapy for this patient Our patient was asymptomatic, had stable cirrhosis, Child \200\223Pugh A (see Case 8), but significant portal hypertension, with a 3.3cm lesion in her liver. The size made it unsuita ble for hepatic resection, and the age of 68 years, with a history of breast cancer, exclud ed her from liver trans- plantation. She underwent local tumor ablation with radiofrequency ablation. A CT scan performed 11 months after ablation showed no local recurrence and no n ew liver lesions (Fig. 14.3). Fig. 14.3 A CT scan 11 months after ablation of the lesion at the tip of the right liver lo be (compare with Fig. 14.1). OXFORD CASE HISTORIES 92 Further reading Talwalker JA, Gores GJ (2004). Diagnosis and staging of hepatocellular carcinoma. Gastroenterology; 127: S126 \200\22332. Llovet JM, Bruix J (2008). Novel advancements in the management of hepatocellular carcinoma in 2008. J Hepatol; 8: S20 \200\223S37. Llovet JM, Ricci S, Mazzaferro V et al. (2008). Sorafenib in advanced hepatocellular carcinoma. N Engl J Med; 359: 378 \200\22390. Lin SM, Lin CJ, Lin CC et al. (2004). Radiofrequency ablation improves prognosis compared with ethanol injection for hepatocellular carcinoma \211 4cm. Gastroenterology; 1 27: 1714 \200\22323. CASE 15 93 Case 15 A 50-year-old female schoolteacher presented to the outpatient department with a 12-year hi story of abdominal pain, straining at stool, a feeling of incom- plete evacuation, and need ing to return to the toilet several times after defeca- tion. She often used per-vaginal di gitation to assist the passage of stool and would spend up to 30 minutes on the toilet at a ny one time. She had seen a dietitian in the past and was on a high-fiber diet and using cr acked linseed sup- plements, and occasional laxatives. Her bowels were currently opening ab out once daily, although \200\230always with difficulty \200\231. She described daily flat us inconti- nence, but denied any fecal incontinence. Prior to the onset of these symp- tom s, her bowels had opened every 1 \200\2232 days with no difficulty. She had a 13-year-old s on (weighing 3700g [8lb 8oz] at birth), born by vaginal delivery with the aid of forceps. S he remembered having a vaginal tear at this time, requiring sutures. Otherwise, her medical history included an epigastric hernia repair 4 years ago, and mild urinary stress incontinence. She had no urinary frequency. On examination, she had a soft abdomen with no palpable masses. Her pulse was 76bpm and she was clinically euthyroid. Perineal examination revealed some perineal descent when the pat ient was asked to strain. Perineal and sacral sensation was normal. Rectal examination reve aled small pellets of firm stool, but was otherwise normal. Sigmoidoscopy showed normal rec tal mucosa. Proctoscopy showed moderate mucosal prolapse but no hemorrhoids. Questions 15a) What is the most likely cause for the patient \200\231s constipation? 15b) What is the differential diagnosis? 15c) How would you further investigate this patient? 15d) What types of laxatives are used for different causes of constipation? OXFORD CASE HISTORIES 94 Answers 15a) What is the most likely cause for the patient \200\231s constipation? The most likely cause of this patient \200\231s constipation is functional outlet obstructi on, due to excessive perineal descent (descending perineum syndrome). The history of strain ing at stool for prolonged periods, feeling of incomplete evacuation, and need for digitati on, are the symptomatic hallmarks. A history of a vaginal delivery of a large baby, requiri ng for- ceps, and symptoms of urinary stress incontinence are also consistent with this dia gnosis. Such a history needs to be elicited empathetically and carefully, primarily by thin king of the possibility rather than dismissing any history of constipation as due to inadeq uate dietary fiber. 15b) What is the differential diagnosis? Every patient with constipation needs a thorough history and careful examination of the per ineum as well as a rectal examination. Systemic symptoms that might suggest hypothyroidism or hypercalcaemia should be considered. The duration of symptoms, maximum interval between defecation, sensitive questioning on the process of defecation, and an appropriate obstetri c history are all important, although not specific for the diagnosis. Examination should in clude inspection of the perineum for any local tear or lesion, a request to strain as if th e bowels were going to open so that perineal descent can be assessed (usually <2cm), assess - ment of sacral sensation (in case of a neurological cause), and rectal examination. Sigmo idoscopy is not essential unless there are symptoms such as bleeding. The differential diag noses shown in Table 15.1 should be considered. 15c) How would you further investigate this patient? Although the history does not suggest a non-gastroenterological cause of constipation, bloo d tests should be carried out for calcium, thyroid function tests, potassium, glucose, and renal function. Blood tests in this lady were normal and symptoms suggested a gastroenterol ogical cause. CT colonography (also known as CT pneumocolon, or virtual colonos- copy) is a ppropriate at this age (our patient was 50) rather than colonos- copy to exclude a structur al cause, because it is non-invasive, generally readily available, and does not need sedati on. Colonoscopy is better reserved for those aged <45 years old, but it is exceptional to f ind anything other than pseudomelanosis coli from the use of stimulant laxatives when the h istory of constipation is so long. The CT colonography in this patient was normal. CASE 15 95 Table 15.1 Differential diagnosis of constipation Cause Comment Non-gastroenterological causes Drugs Specifically ask about analgesics Also consider calcium antagonists, tricyclics, iron supplements, and many others Environment and diet Ask about soluble dietary fiber (linseed is more effective than bran), access to the toilet (delay can reduce the urge to defecate), and consider poor mobility as a contributing fact or Occupational exposure to lead still occurs Endocrine and metabolic Hypothyroidism, hypercalcaemia, hypopituitarism, diabetes, hypokalaemia, rarely uraemia Always check thyroid function, calcium, and electrolytes Neuromuscular Parkinson \200\231s disease, autonomic neuropathy (usually diabetic), or spinal cord damage are occasional causes, but it is important to consider a lesion in the conus if constipati on is progressive or associated with nocturnal back pain Many rare myopathies are associated with constipation Psychiatric conditions Constipation can be a feature of the psychomotor retardation of depression. Gastroenterological causes Structural Pain from an anal fissure or obstruction due to a neoplasm (may be pelvic rather than color ectal), stenosis from diverticular or Crohn \200\231s disease, volvulus, or intussusception (may be rectal-rectal intussusception) Functional Normal transit means constipation-predominant irritable bowel syndrome normal transit Slow transit is life-long and associated with extreme intervals between defaecation (often >1 week). Transit studies using radio-opaque markers are appropriate if the interval betwee n defaecation is >5 days slow transit functional outlet obstruction Functional outlet obstruction is suspected from the history and is an indication for defeca tion proctography to image the dynamics of defaecation A functional cause seemed likely. A transit study is always indicated, as history alone doe s not discriminate between slow transit constipation and functional outlet obstruction. A d efaecating proctogram (Fig. 15.1) showed 4cm descent of the perineal body during evacuation , a large anterior rectocele, and a recto-rectal intussusception. Thirty percent of the ins tilled barium paste was retained after evacuation. OXFORD CASE HISTORIES 96 Fig. 15.1 Single lateral image from a defecating proctogram showing intra-rectal intussuscp tion (long arrows) and a mod- erate anterior rectocele (short arrows). The radiological appearance was consistent with functional outlet obstruction due to the de scending perineum syndrome. Anorectal man- ometry showed a low anal sphincter resting press ure and endoscopic ultrasound (Fig. 15.2) identified a defect in the external anal sphincte r. The internal sphincter was normal. The history and investigations were consistent with a defaecation dis- order, although it m ay be debated whether a dynamic anatomical change causing obstruction is best classified as \200\230structural \200\231 or \200\230functional \200\231. Treatment includes biofeedback therapy, appropriate use of laxatives (15d), and surgery. Bi ofeedback therapy is only available at specialist centers. When a cause can be anatomically defined, patients are best referred to a colorectal surgeon with an interest in pelvic flo or disorders for discussion about surgical intervention, although surgery is not appro- pri ate for all patients. The decision about when not to operate for dynamic obstruction is as important as a decision to operate. Our patient underwent a laparoscopic anterior mesh rectopexy to correct her recto-rectal in tussusception and had a good result. Three months after surgery bowels were opening once da ily, with no sensation of incomplete evacuation and no need to digitate. 15d) What types of laxatives are used for different causes of constipation? There are four groups of laxatives and over 60 different preparations (Table 15.2), but adj usting dietary fiber intake and an osmotic laxative, with only an occasional stimulant, wor k for most. The diagnosis should be reassessed if two sorts of laxative are ineffective. An y laxative is dangerous in mechanical obstruction. CASE 15 97 External anal sphincter Fig. 15.2 Defect in the external anal sphincter (circled). Table 15.2 Different types of laxatives Type Comment Bulk-forming laxatives For constipation-predominant irritable bowel syndrome or painful anorectal conditions, with extra fluid, isphagula husk (Fybogel ) can be prescribed, but is relatively expensive. Golden or cracked linseed, available in the cereal section of any supermarket, are good sou rces of soluble fiber that take up water readily. Fiber usually makes symptoms from neuropathic, structural, slow-transit constipation, or de faecation disorders worse Osmotic laxatives Indicated when bulk-forming laxatives are ineffective Lactulose (30 \200\223100mL/day, often too little given), polyethylene glycol 3350 (Movicol 1 \200\2233 sachets/day), or sodium picosulphate (Laxoberal , 5 \200\22320mL/day availa ble over the counter in the UK) Generally take several days to work and need to be taken on a regular basis and the dose ad justed according to effect Stimulant laxatives For opioid-induced constipation, bowel clearance, neurological disorders or temporary use i n stubborn constipation Long-term use should be avoided Anthraquinones (e.g. Senna \200\223 2 \200\2234 tablets at night), bisacodyl (e.g. Dulcola x 5 \200\22310mg at bedtime), or codanthrusate (1 \200\2233 capsules, or 5 \200\22315mL at night) are appropriate for patients on long-term morphine, but the latter carries a small c arcinogenic risk (continued) OXFORD CASE HISTORIES 98 Table 15.2 (continued) Different types of laxatives Type Comment Fecal softeners For stubborn constipation Glycerin suppositories or an enema (e.g. Micralax , or Fleet Ene ma) can be given 2 \200\2233 times a week to prevent recurrent fecal impaction Docusate sodium (100mg capsule once or twice daily, or as a liquid) is modestly effective Further reading D \200\231 Hoore A, Penninckx F (2003). Obstructed defaecation. Colorectal Dis; 5: 280 \200 \2237. Andromanakos N, Skandalakis P, Troupis T, Filippou (2006). Constipation of anorectal outlet obstruction: Pathophysiology, evaluation and management. J Gastroenterol Hepatol; 2 1: 639 \200\22346. Muller-Lissner S (2007). The difficult patient with constipation. Best Practice Research Cl in Gastro; 21: 473 \200\22384. CASE 16 99 Case 16 A 53-year-old South African woman was being followed up in cardiology clinic for ischaemic heart disease. She had been feeling unwell in the preceding week, with nausea and vomiting accompanied by general malaise. She had not recently traveled. She smoked 15 cigarettes per day. Her son, with whom she lived, had had a flu-like illness in the preceding weeks. On examination, she was jaundiced. She had a tender liver, but no signs of chronic liver disease. Investigations showed: 9/L, platelets 143 x 109/L mol/L Hb 18.4g/dL, WCC 7.0 x 10 Na 137mmol/L, K 4.1mmol/L, creatinine 79 mol/L , AST 1160 IU/L, ALT 3422 IU/L, albumin 39g/L Bilirubin 95 Prothrombin time 15 sec INR 1.3 Blood movie: plasma cells noted. Questions 16a) What is the differential diagnosis and what investigations are indicated? 16b) Considering the results given in Answer 16a), discuss the clinical course of this disease. 16c) Discuss the transmission and prevention of this disease. 16d) What is the significance of the plasma cells seen on the blood movie? OXFORD CASE HISTORIES 100 Answers 16a) What is the differential diagnosis? The differential diagnosis is that of an acute hepatitis. This includes acute viral hepatit is, autoimmune liver disease, drug toxicity (see Case 1) and in view of her ischaemic heart disease, it is important to consider ischaemic hepatitis. Ischaemic hepatitis is usually s een in patients with congestive heart failure who become hypotensive. It is a result of hep atic venous outflow obstruction combined with reduced hepatic arterial blood flow. In the a bsence of risk factors for acute hepatitis B infection, such as intravenous drug use, unscr eened blood products or sexual expo- sure, the most common viral causes are hepatitis A and hepatitis E. Epstein \200\223Barr virus and cytomegalovirus are uncommon causes in this ag e group. Alcoholic hepatitis does not cause a pronounced transaminitis (ALT is almost alway s <300 IU/L). The pronounced transaminitis is most consistent with a viral cause. An ultrasound scan of the abdomen was unremarkable. HAV IgM positive, HBsAb negative, HBsAg negative Antinuclear antibody negative, anti-smooth muscle antibody nega- tive, IgG 10.9g/L. 16b) Discuss the clinical course of this disease. The patient has acute hepatitis A. The incubation period after ingestion of the virus is 15 \200\22350 days (mean 28 days). Patients typically have a flu- like prodrome that starts s uddenly, lasts 5 \200\2237 days, and may be accompa- nied by nausea and vomiting. This is f ollowed by jaundice. Fecal shedding of viral particles is greatest in the prodrome, with ma rked reduction in viral excretion after the onset of jaundice. Viraemia occurs. The onset o f jaundice is preceded by darkening of urine. Clinically there may be mild enlargement of t he liver, which is often tender. Serum transaminases may be elevated up to 100 times the up per limit of normal. The bilirubin is usually <170 mol/L. Symptomatic disease occurs more frequently and is more severe in adults: 70% develop symptoms with jaundice, whereas 70% of children under the age of 6 years will be asymp- tomatic. Even if young children have vira l symptoms, they rarely become jaundiced. Most illnesses resolve completely within 3 \200 \2236 months. Occasionally hepatitis A may be complicated by acute liver failure, prolonged cholestasis o r relapse. Acute liver failure occurs in <1% of patients and typically presents with progre ssive jaundice and subse- quent encephalopathy. Risk factors include the elderly and those with CASE 16 101 pre-existing liver disease. Mortality is up to 95% without liver transplan- tation. Indicat ors of a poor prognosis once acute liver failure has devel- oped include age >40 years or < 10 years, jaundice for more than 7 days prior to encephalopathy, serum bilirubin >291 mol/ L, and prothrombin time >25 sec. Prolonged cholestasis is uncommon, but is associated with worsening jaundice (bilirubin >340 mol/L), increasing ALP, reduc- tion in ALT, and predomi nant pruritus. It may persist for months, but complete resolution usually occurs. Relapse o f hepatitis rarely occurs weeks or months after initial resolution of hepatitis. Symptoms a nd transaminitis may be similar to the initial episode. The prognosis is good. Treatment of hepatitis A is supportive. Admission is indicated for severe cases with hepati c decompensation, or if there is dehydration and electrolyte imbalances secondary to vomiti ng. Avoidance of hepatic toxins (alcohol, paracetamol) is advisable. 16c) Discuss the transmission and prevention of this disease. Transmission is enteric (fecal \200\223oral) and the usual source of contact is within a ho usehold in endemic areas. Up to 50% of household members of an index case may acquire infec tion without prompt and meticulous preventive measures. Daycare centers for babies and smal l children are an important source of infection. Epidemics are associated with poor sanitat ion, overcrowding, and low socioeconomic status. Sporadic out- breaks may be associated wit h a single source, shared by large numbers of people (such as drinking water or contaminate d food). Contact with sewage (occupational or incidental), ingestion of uncooked shellfish, and travel by non-immune individuals to endemic areas are well-recognized risk factors and should be identified by a careful history. In low-prevalence areas, outbreaks are mainly f ood borne. Intravenous drug use is a risk factor through poor living conditions, although p arenteral transmission by contaminated blood products has been documented. Prevention is through adequate sanitation, primary vaccination, and post-exposure prophylax is. An important component of secondary pre- vention is notification of local authorities o f an index case. Hepatitis A is a notifiable disease. Even before HAV serology was available, passive immunization with human immunoglobulin cont aining anti-HAV IgG was the mainstay of prophylaxis. Since 1992, inactivated HAV vaccine ha s been available in Europe (Havrix ). A second vaccine (Vaqta ) became available in 1996. Vaccine is given in two separate doses. After a single dose, 100% of OXFORD CASE HISTORIES 102 people will have protective antibodies at 6 months. This persists for at least 1 year. A se cond dose provides effective immunity for up to 20 years. Antibody concentration in the ser um after two doses of vaccine may be as high as those seen following natural infection. Vaccination has markedly reduced the incidence of hepatitis A. Annual cases reported to the Centers for Disease Control in the USA have dropped from 30,000 before the introduction of vaccination to <4000 in 2006. Hepatitis A vaccination is part of the routine childhood vac cination schedule in the USA, given by the time the child is 2 years old. This is not the p ractice in all countries. Specific indications for immunization include travel from areas o f low prevalence to areas of high prevalence, underlying chronic liver disease, clotting fa ctor deficiencies requiring frequent administration of blood products, and intravenous drug use. Epidemic outbreaks in a community can be rapidly terminated by blanket immunization. Intramuscular injection of pooled human immunoglobulin is effective post-exposure prophylax is when given within 2 weeks of contact with an index case. Even if infection is not preven ted, it is attenuated. The passive immunity lasts about 3 months. In people with IgA defici ency, immu- noglobulin is contraindicated, due to the risk of anaphylaxis. It may be given during pregnancy or lactation and no viral transmission has been documented. A trial of vac cination versus immunoglobulin for post- exposure prophylaxis showed no difference between the two. The advan- tage of vaccination is the cost, availability, and long-lasting immunit y. Our patient had acquired the infection from her son. Since he had subclinical disease, his source could not be identified. Had his condition been diagnosed, post-exposure prophylaxis would have been desirable due to the increased risk of complicated disease at her age, but fortunately she made an uneventful recovery. 16d) What is the significance of the plasma cells seen on the blood movie? Peripheral plasmacytosis is usually a manifestation of a plasma cell dyscrasia (myeloma). T his should be excluded in any patient with plasma cells on peripheral blood movie. A reacti ve peripheral plasmacytosis has been described in association with other malignancies, auto immune disease, and infections including septicaemia, EBV infection, parvovirus B19 infecti on, and dengue fever. It has also been described in association with acute hepatitis A. CASE 16 103 Our patient had normal protein electrophoresis, no Bence \200\223Jones pro- teinuria, and a normal bone marrow examination. The plasmacytosis was transient and resolved spontaneously . Further reading Baker CJ (2007). Another success for hepatitis A vaccine. N Engl J Med; 357(17): 1757 \200 \2239. Gupta A, Chawla Y (2008). Changing epidemiology of hepatitis A infection. Indian J M ed Res; 128: 7 \200\2239. Koff RS (1998). Hepatitis A. Lancet; 351: 1643 \200\2239. Victor JC, Monto AS, Surdina TY e t al. (2007). Hepatitis A vaccine versus immune globulin for post-exposure prophylaxis. N Engl J Med; 357: 1685 \200\22394. Wada T, Maeba H, Ikawa Y et al. (2007). Reactive peripheral blood plasmacytosis in a patient with acute hepatitis A. Int J Hematol; 85: 191 \200\2234. OXFORD CASE HISTORIES 104 Case 17 A 30-year-old woman came to seek advice about her risk of cancer. Her mater- nal aunt had j ust been diagnosed with bowel cancer at 43 years of age, and her mother had been treated fo r endometrial cancer over 15 years ago. Her father, 35-year-old brother, and 25-year-old si ster were both well. Her maternal grandparents died at a young age in a motor vehicle accid ent. Her paternal grandparents were alive and well, with no history of malignancy. She went on to have a colonoscopy which discovered a poorly differentiated adenocarci- noma in the ascending colon. Questions 17a) What is the name of the most likely syndrome? 17b) What clinical criteria should raise suspicion of this syndrome? 17c) How is the syndrome best diagnosed? 17d) What surveillance should the patient be offered? 17e) Who in this patient \200\231s family should be screened and by what method? This page intentionally left blank OXFORD CASE HISTORIES 106 Answers 17a) What is the name of the most likely syndrome? The most likely syndrome is Lynch Syndrome (hereditary non-polyposis colorectal cancer, als o known as HNPCC). Approximately 10 \200\22315% of patients with colorectal cancer have a f amily history of colorectal cancer, while only 5% have a family history of early onset (<45 years) colorectal cancer. In this situation, a combination of environmental and genetic fa c- tors plays a role, but in a small fraction of cases, genetic factors play a dom- inant r ole. Lynch syndrome is the most common inherited form of colorectal cancer. The syndrome is due to a mutation in one of the mis- match repair genes: MSH2, MLH1, MSH6, PMS2, which lea ds to multiple errors in repetitive DNA sequences (microsatellites) throughout the genome o f tumors. This instability is called microsatellite instability (MSI). The cardinal features of Lynch syndrome are: de novo mutation is very rare, unlike Autosomal dominant inheritance: in familial adenomatous polyposis Associated cancers: endometrium, stomach, ovary, ureter/renal pelvis, brain, small bowel, h epatobiliary tract, pancreas, or skin cancers Development of colorectal cancer at an early age Development of multiple cancers (synchronous colorectal cancers \200\223 occurring in more than one site at the same time, or metachronous \200\223 occurring after an interval) Features of colorectal cancer: located in the proximal colon; may be multiple (synchronous) tumors; have an improved survival com- pared with sporadic cancers at a young age, althoug h more often poorly differentiated Features of adenomas: the number may vary from one to a few; a higher proportion have villo us growth pattern or mucinous histology; tendency to have a high degree of dysplasia with r apid progression from adenoma to carcinoma High frequency of MSI identified by MSI analysis Immunohistochemistry: characterized by loss of MLH1, MSH2, MSH6, or PMS2 protein expression 17b) What clinical criteria should raise suspicion of this syndrome? The Revised Bethesda Criteria are used to identify individuals suspected of having Lynch sy ndrome. If a patient meets just one of these criteria (Table 17.1), it is an indication for molecular genetic studies either by CASE 17 107 analysis of MSI in the tumor DNA, or immunohistochemical analysis of mismatch repair protei ns. See also the Amsterdam II Criteria (Table 17.2). The lifetime risk for carriers of a mismatch repair (MMR) gene varies from 30% to 80%. Risk depends on gender and type of MMR gene involved. For females, the risk of endometrial canc er is 30 \200\22360%. Risk of other cancers is 10 \200\22315%. 17c) How is the syndrome best diagnosed? The mainstay of diagnosis of Lynch syndrome remains an accurate family history. Clinicians should suspect the condition in patients with early onset malignancy or multiple malignanci es. Such patients are best referred to specialist family cancer clinics. If the Bethesda cr iteria are met by the index case, immunohistochemical analysis for MMR protein expression i s appropriate, as well as examination of tumor DNA for MSI. When grading MSI in colorectal tumors, the tumor is referred to as MSI-high when two of the five markers show instability. If only one of the markers shows instability, the tumor is referred to as MSI-low. If none of the markers show instability, the tumor is referred to a s MSI- stable. Immunohistochemistry demonstrates loss of function of the MMR proteins by co mparing normal host tissue to that of the tumor. 17d) What surveillance should the patient be offered? Surveillance for this patient would include annual or biennial colonos- copy, because the r isk of a metachronous colorectal cancer is high. The risk for developing an invasive colore ctal cancer within a 2-year period is, however, very small. It remains uncertain whether su btotal colectomy should be performed instead of segmental resection in Lynch Table 17.1 Revised Bethesda criteria for suspected Lynch syndrome Colorectal cancer diagnosed in a patient <50 years of age Presence of synchronous or metachronous colorectal cancer, or other Lynch-related tumor in the same patient, regardless of age Colorectal cancer with microsatellite instability ( \200\230MSI-high \200\231,) diagnosed i n a patient <60 years of age Patient with colorectal cancer and a first-degree relative with a Lynch syndrome-related tu mor, when one of the cancers was diagnosed <50 years of age Patient with colorectal cancer with two or more first-degree or second-degree relatives wit h a Lynch syndrome-related tumor, regardless of age