improvement in liver histological analysis with weight loss. Hepatology; 39: 1647 \200\2235 4. Garcia-Compean D, Jaquez-Quintana JO, Gonzalez-Gonzalez JA, Maldonado-Garza H (2009). Liver cirrhosis and diabetes: risk factors, pathophysiology, clinical implications and management. World J Gastroenterol; 15: 280 \200\2238. OXFORD CASE HISTORIES 308 Case 46 A 68-year-old woman presented with a 10-day history of a flu-like illness fol- lowed by a w eek of jaundice. She complained of lethargy, myalgia, and nausea, but no vomiting. She had lost no weight. She lived on a small holding with her husband and kept livestock, including sheep and goats. She had epilepsy for which she was taking carbamazepine. On examination, she looked ill. Her Glasgow Coma Score was 15, but she was dehydrated and j aundiced. Her pulse was 110bpm and blood pressure 90/60mmHg. Her temperature was 38 C. Exa mination of the abdomen was unremarkable. Investigations showed: 9/L, neutrophils 10 x 109/L, platelets 27 x Hb 10.6g/dL, WCC 12 x 10 109/L Blood movie: left shift of myeloid cells, peripheral plasma cells Prothrombin time 18 sec Haptoglobin 1.9g/L mol/L Na 123mmol/L, K 3.0mmol/L, urea 31mmol/L, creatinine 280 mol/L, ALT 24 IU/L, ALP 279 IU/L, albumin 32g/L Bilirubin 208 CRP 133g/L Abdominal ultrasound showed a large stone in the gallbladder, with prominent intrahepatic b ile ducts, but normal extrahepatic ducts. Normal spleen and kidneys. Questions 46a) Describe how you would establish a diagnosis. 46b) What is particularly notable in the history? 46c) How do we treat this condition? 46d) What are the complications and outcomes of this condition? This page intentionally left blank OXFORD CASE HISTORIES 310 Answers 46a) Describe how you would establish a diagnosis. Presentation with flu-like symptoms, fever, and jaundice suggests an infectious cause. This is supported by the markedly elevated CRP and leucocytosis with prominent neutrophilia and left shift. Bacterial infections with septicaemia should first be considered, including as cending cholangitis, pneumonia, or urinary tract infections. A raised ALP is common with sy stemic bacterial infection, but cholangitis can also occur with only mildly elevated ALP. B lood cultures are manda- tory and should be followed by empiric therapy with broad-spectrum antibiotics. Acute viral hepatitis may present with a similar syndrome, but the ALT was normal in this c ase. Hepatitis A (see Case 16), hepatitis B, and hepatitis E commonly present with acute he patitis. Epstein \200\223Barr virus infection may cause jaundice in 10% of cases but is usu ally contracted in childhood or early adulthood. There were no risk factors for parenterall y or enterically transmitted hepatitis. There is also a marked disparity between the renal impairment and severity of liver dysfunction, since the prothrombin time was only mildly pr olonged. Renal impairment is only associated with severe hepatitis. A travel history is important, because other infections should be con- sidered, including m alaria and rickettsial infection. Our patient had not recently traveled, but she had been i n contact with animals. 46b) What in the history is specifically significant? The close contact with farm animals is relevant. Brucellosis has to be considered since the patient kept sheep and goats. Brucella melitensis is associated with goats and B. ovis wit h sheep. Either is acquired from contact, including unpasteurized milk, and present with an acute febrile illness (B. melitensis is named after David Bruce, who identified this organ ism as the cause of Malta Fever). When severe the illness may be associated with jaundice, but the ALP is usually raised since brucellosis causes granulomatous hepatitis (see Case 42 ). The most likely diagnosis was leptospirosis. This characteristically causes a disproportion ately high bilirubin compared with the ALT and ALP. Where there are farms there are rats an d the ubiquitous spirochete, Leptospira interrogans, is specifically associated with rats. A wide range of mammals may harbor the organism in the renal tubules, including cattle, dog s (which become severely ill), pigs, and all kinds of rodents. CASE 46 311 Rodents are the most important vector. The organism is transmitted through direct contact w ith infected urine, or indirectly through contact with contaminated water or soil. Leptospi ra survive in the environment for long periods if conditions are wet. Occupational exposure occurs in vets, farmers, rat catchers, sewage or slaughterhouse workers, and recreational exposure occurs during immersion in contaminated rivers or lakes. The diagnosis is made through dark field microscopy or culture of urine. In the first (lept ospiraemic) phase of the illness, blood cultures may be positive and in the second (immune) phase urine culture may be positive. The diagnosis is frequently considered late in the il lness. A sero- logical agglutination test is the reference method, but requires a 4-fold ri se in titres to be diagnostic, so two samples separated by an interval of 10 days are neede d. Recent seroconversion may be demonstrated by ELISA methods that detect IgM antibodies. Investigations showed: Leptospira ELISA IgM positive 1:2560 Leptospira microscopic agglutination test positive at 1:2560 Blood cultures were negative, probably because they were taken in the second phase of the i llness. 46c) How do we treat this condition? Leptospira spp. are sensitive to most antibiotics, with the exception of chloramphenicol. M ild illness may be treated with oral doxycycline. Severe illness should be treated intraven ously with either penicillin G 1.5 million units 6-hourly, or ampicillin 1g 6-hourly if the diagnosis is established. In the absence of an established diagnosis, a broad-spectrum ant ibiotic should be used. A third-generation cephalosporin was a rea- sonable choice in our p atient. This patient was started on intravenous fluids and cefotaxime 1g 3 times a day IVI on admis sion, following appropriate procurement of blood cultures and before serology results were known. Improvement in all respects occurred over the following 3 days, and she survived the ill- ness without permanent sequelae. 46d) What are the complications and outcomes of this condition? Leptospirosis classically has two phases. The leptospiraemic phase fol- lows direct exposur e, commonly through intact skin, after a 7 \200\22314-day incubation period. Blood cultures may be positive, and it characteristi- cally causes a flu-like illness, with fever, intens e myalgia, headache, OXFORD CASE HISTORIES 312 anorexia, nausea, vomiting, lymphadenopathy and conjunctival injec- tion. Conjunctival inje ction is an important clue, as it is particularly characteristic. Myalgia is frequently sev ere, especially with L. hajji caught from cattle, particularly affecting the calves, back a nd abdominal mus- cles. This is followed by a period of up to 3 days when the fever subside s, before the onset of the immune phase. Organisms may then be present in the urine, but le ptospiraemia is over. A second clinical phase does not occur in mild cases, but when it doe s there is hepatorenal and pulmo- nary symptoms. Weil \200\231s disease is the combination of jaundice, spleno- megaly, and renal failure in a patient with leptospirosis (classically L. icterohaemorrhagiae). Pulmonary involvement is indicated by a non- specific cough and d yspnoea, but severe pulmonary hemorrhage can occur that may be fatal. Leptospirosis needs to be differentiated from viral haemorrhagic fever (Lassa, Marburg, and Ebola) when the illness presents with petichiae, purpura and epistaxis, but the travel his tory is usually then the clue to diagnosis. Severe gastrointestinal and intracranial hemorr hage, haemo- lysis, cardiac involvement, ARDS, rhabdomyolysis, and pancreatitis have been d escribed but are rare. Ninety percent of symptomatic disease is mild, but severe cases may be associated with a mo rtality of 40%. Poor prognostic markers include hypotension, oliguria, hyperkalaemia, metab olic acidosis, dyspnoea, cough, haemoptysis, alveolar lung infiltrates, WCC >12.9 x 109/L, and thrombocytopenia. Liver failure is usually not the cause of death. Patients who survive make a full recovery of liver and renal function, although residual hypertension has been reported. Further reading Ahmad SN, Shah S, Ahmad FMH (2005). Laboratory diagnosis of Leptospirosis. J Postgrad Med; 51: 195 \200\223200. Bal AM (2005). Unusual clinical manifestations of Leptospirosis. J Postgrad Med; 51: 179 \200\22383. Kaul DR, Flanders SA, Saint S (2005). Clinical problem-solving. Clear as mud. N Engl J Med; 352: 1914 \200\22318. Vijayachari P, Suqunan AP, Shriram AN (2008). Leptospirosis: an emerging global health problem. J Biosci; 33: 557 \200\22369. This page intentionally left blank OXFORD CASE HISTORIES 314 Case 47 A 20-year-old woman presented with a 3-day history of jaundice, nausea, and abdominal disco mfort. She had noticed dark urine, but had normal stool and no itch. She was born in Poland and had been for a 2-week holiday to Thailand, returning 2 weeks ago. She had previously b een fit and well, and was on no medication. She drank <10 units/week. Examination was norma l apart from jaundice. Investigations showed: 9/L (10.5 neutrophils), platelets 171 x 109/L mol/L Hb 9.5g/dL, WCC 14 x 10 Na 133mmol/L, K 3.7mmol/L, urea 4.2mmol/L, creatinine 98 mol/l, AST 43 IU/L, ALT 69 IU/L, ALP 130 IU/L, Bilirubin 377 albumin 28g/L CRP normal Prothrombin time 26 sec. On examination the following day, she looked well, apart from deep jaundice. There was no e ncephalopathy. Urine output was <30ml/hour. Further investigations: 9/L, platelets 144 x 109/L Hb 7.0g/dL, WCC 21.8 x 10 Blood movie: polychromasia, burr cells, microspherocytes; no fragmented cells Reticulocytes 6.7% (normal range <2%) Prothrombin time 30 sec mol/L Na 134mmol/L; K 4.8mmol/L; creatinine 164 mol/L; AST 59 IU/L, ALT 42 IU/L, ALP 69 IU/L, Bilirubin 489 albumin 23g/L Abdominal ultrasound: no comment on liver texture, splenomegaly (14cm). Questions 47a) What is the diagnosis? 47b) How is the condition usually diagnosed? 47c) What is the treatment? 47d) What other symptoms can this disorder present with? 47e) Should siblings be screened and if so how? This page intentionally left blank OXFORD CASE HISTORIES 316 Answers 47a) What is the diagnosis? The diagnosis is acute liver failure due to Wilson \200\231s disease. All other causes of a cute liver failure should be considered (see Case 1) and a full liver screen should be carr ied out, but the haemolysis is characteristic of Wilson \200\231s disease. Wilson \200\231s disease is a rare autosomal recessive disorder of copper metabolism. The major physiologic al aberration is excessive absorption of copper from the small intestine and decreased excr etion of copper by the liver. The genetic defect, localized to chromosome 13q, affects the copper-transporting adenosine triphosphatase gene (ATP7B) in the liver. The process of inco rporating copper into caeruloplasmin and excretion of excess copper into bile is impaired i n Wilson \200\231s disease. As liver copper levels increase, copper is released into the ci rculation and deposited in other organs. Symptoms generally present from 6 years to 40 years of age. Hepatic dysfunction is the pres enting feature in more than half of patients. The three major patterns of hepatic involveme nt are: Chronic hepatitis (elevated transaminases) Cirrhosis (the most common initial presentation) Acute hepatic failure. This case presented with acute hepatic failure and severe coagulopathy; encephalopathy can occur. Acute intravascular haemolysis and early renal failure are clues to the diagnosis. H aemolysis is due to rapid release of copper into the circulation, which also causes acute r enal tubular dys- function. Acute viral hepatitis is usually the working diagnosis, because the patient is not suspected of having underlying liver disease. An impor- tant clue to Wi lson \200\231s disease is the disproportionately low serum AST (usually much less than 1500 IU/L), which would be exceptional in acute viral hepatitis. The ALP is usually in the norm al range or even low for age, and the serum bilirubin is disproportionately elevated becaus e of haemolysis. However, biochemical indices are not specific. The acute presentation of W ilson \200\231s disease is more common in women than in men (4:1 ratio). 47b) How is the condition usually diagnosed? The diagnosis is confirmed by measurement of serum caeruloplasmin, urinary copper excretion , hepatic copper content, and the detection of Kayser \200\223Fleischer rings. A patient wi th the classic combination of chronic CASE 47 317 liver disease, tremor or dystonia, and Kayser \200\223Fleischer rings is readily diagnosed, but such patients are exceptional. There are two major disturbances of copper deposition i n Wilson \200\231s disease: a reduction in the rate of incorporation of copper into caerulo plasmin, and a decrease in the biliary excretion of copper. Table 47.1 shows typical levels in a patient with Wilson \200\231s disease compared with the normal reference ranges. Serum caeruloplasmin: many patients with Wilson \200\231s disease have a caeruloplasmin wit hin the normal range. Caeruloplasmin is an acute phase protein, and increases in response t o inflammation, pregnancy, estrogen use, or any infection. Falsely low caeruloplasmin conce n- trations may occur in any protein deficiency state, including neph- rotic syndrome, mala bsorption and protein-losing enteropathy. Caeruloplasmin levels may also be low in 10 \200 \22320% of heterozygotes for the Wilson \200\231s disease gene, but who do not develop the disease and do not require treatment. Serum copper concentration is low, in parallel with the low serum caerulo- plasmin, in most patients with Wilson \200\231s disease. Very high levels are detected in acute liver failu re, because of rapid release of copper from the liver. Urinary copper excretion rate is >10 0 g/d (reference range, <40 g/d) in most patients with symptomatic Wilson \200\231s disea se. The rate may also be elevated in other cholestatic liver diseases. Both the sensitivity and the specificity of this test are insufficient for it to be used as a screening test, b ut it usefully confirms the diagnosis and helps to evaluate response to chelation therapy. A provocative test of urinary copper excretion in which penicillamine (500mg orally every 1 2 hours) is given while a 24-hour urinary collection is obtained sometimes provides useful infor- mation: a normal person excretes as much as 20 times the baseline level Table 47.1 Copper measurements in Wilson \200\231s disease and normal individuals Measurement Wilson \200\231s disease Normal adults Serum caeruloplasmin Serum copper ( g/L) ( mol/L) Urinary copper ( g/day) ( mol/day) Li ver copper ( g/g dry weight) 0 \200\223200 200 \200\223350 190 \200\223640 700 \200\2231520 3 \200\22310 11 \200\22324 100 \200\2231000 <40 >1.6 <0.6 >200 20 \200\22350 OXFORD CASE HISTORIES 318 after penicillamine, but a urinary excretion of >25 mol of copper 24 hours after penicilla mine is diagnostic of Wilson \200\231s disease. Hepatic copper concentration is the gold standard for diagnosis of Wilson \200\231s disease . A liver biopsy with sufficient tissue reveals levels >250 g/g of dry weight, even in asy mptomatic patients. This assumes the absence of cholestatic liver disease, which leads to r educed biliary secretion and copper accumulation in the liver. A normal hepatic copper conc entration (reference range 15 \200\22355 g/g) effectively excludes the diag- nosis of untr eated Wilson \200\231s disease. Kayser \200\223Fleischer rings: slit-lamp examination may reveal Kayser \200\223 Fleischer rings. These are found at the limbus and are caused by copper deposition in Descemet \200 \231s membrane in the cornea. A careful slit-lamp examination is mandatory and can be the m ost rapid way of making the diagnosis: it is only visible on direct inspection when iris pi gmentation is light and copper deposition is heavy. Kayser \200\223Fleischer rings are obse rved in up to 90% of individuals with symptomatic Wilson \200\231s disease, and are almost invariably present in patients with neurological manifestations. Kayser \200\223Flesicher r ings may be absent in 10 \200\22350% of patients with exclu- sively hepatic involvement, an d in presymptomatic patients. Consequently, the absence of Kayser \200\223Flesicher rings d oes not exclude the diagnosis, and are no longer considered pathognomonic of Wilson \200 \231s disease unless accompanied by neurological manifestations. They have been observed in patients with chronic cholestatic disorders, such as partial biliary atresia, primary bili ary cirrhosis, and primary sclerosing cholangitis. 47c) What is the treatment of this condition? Patients with fulminant hepatic failure from Wilson \200\231s disease need immediate referr al for liver transplantation, because such patients do not respond well to chelation treatm ent. Patients with a prognostic index (Table 47.2) of >7 should be consid- ered for liver transp lantation. Our patient had a score of 8. Most patients who exceed a score of 7 die within 2 months of diagnosis unless they have a liver transplant. Prognosis after liver transplanta tion is good. In a study of 55 patients with Wilson \200\231s disease who underwent transpl antation, the 1-year survival rate was 79%, and overall survival rate was 72% 20 years afte r transplantation. The mainstay of therapy for Wilson \200\231s disease is the use of chelating agents and med ications that block copper absorption from the gastroin- testinal tract (Table 47.3). There are three recognized treatments: CASE 47 319 Table 47.2 Prognostic index in fulminant Wilson \200\231s disease Score 0 1 2 3 4 Serum bilirubin (mmol/L) <100 100 \200\223150 151 \200\223200 201 \200\223300 >300 Serum AST (IU/L) <100 100 \200\223150 151 \200\223200 201 \200\223300 >300 Prolongation of prothrombin time (seconds) <4 4 \200\2238 9 \200\22312 13 \200\22320 >30 Penicillamine Trien (trientine) Zinc. With effective chelation therapy, most patients live normal, healthy lives. Early treatment is critical, and outcome is best for patients in whom the disease is diagnosed and treatme nt initiated before the disease causes symptoms. There is a potential role for gene transfe r therapy in the future. 47d) What other symptoms can this disorder present with? Neuropsychiatric: most patients who have neuropsychiatric manifesta- tions also have cirrho sis. The most common neurological feature Table 47.3 Medical treatment of Wilson \200\231s disease Drug Mechanism Dose Monitoring for efficacy Monitoring for side effects Penicillamine Increases urinary excretion of copper Initially 1 \200\2231.5g/d, Urinary copper excretion 500 \200\223800 g/d Full blood count (thrombocytopenia, leucopenia, aplastic anemia) Maintenance: 1g/day Estimated non-caeruloplas- min-bound copper <100 g/L Urinalysis (proteinuria) Examine skin for rashes Trientene Increases urinary excretion of copper 1 \200\2231.2g/day As with penicillamine Full blood count Iron studies May impair intestinal absorption of copper Zinc Interferes with copper absorption, increases copper excretion in stools Initially 50mg three times/day 24-hour urinary copper 200 \200\223400 g/day Serum Zn Maintenance: titrate against efficacy Estimated non- caeruloplasmin bound copper <100 g/L OXFORD CASE HISTORIES 320 is asymmetric tremor, occurring in half of individuals with Wilson \200\231s disease. The c haracter of the tremor is variable and may be predomi- nantly resting, postural, or kinetic . Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, mask-l ike facies, clumsi- ness, and personality changes. Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidit y, and flexion contractures. Psychiatric features include emotional lability, impulsiveness , disinhibition, and self-injurious behavior. About 10 \200\22320% of patients present with psychiatric symp- toms and the cause may be overlooked. Musculoskeletal: osteopenia is common in Wilson \200\231s disease. An arthrop- athy resembl ing premature osteoarthritis generally involves the spine and large appendicular joints, su ch as knees, wrists, and hips. Symptomatic joint disease occurs in 20 \200\22350%, usually late in the course of the disease and frequently > 20 years of age. Osteochondritis disseca ns, chondroma- lacia patellae, and chondrocalcinosis have also been described. Hematological: haemolytic anemia is a rare (10 \200\22315%) but character- istic complicati on of the disease, usually in conjunction with acute hepatic presentations. Renal: the gene is expressed in kidney tissue, so any renal manifestations may be primary o r secondary to release of copper from the liver. Patients resemble those with Fanconi \200 \231s syndrome, with defective renal acidifica- tion and excess renal losses of amino acids , glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. Urolithiasis, f ound in up to 16% of patients, may result from hypercalciuria or poor acidification. Haemat uria and nephrocalcinosis are reported, as are proteinuria and peptiduria. Both can occur a s part of the disease process or after therapy as an adverse effects of penicillamine. 47e) Should siblings be screened and if so how? More than 300 mutations in the ATP7B gene for Wilson \200\231s disease have been detected. Genetic markers that closely flank the gene are used for pre-symptomatic diagnosis of sibli ngs of a known patient, when the patient and parents are available for testing. Overt sympt oms of Wilson \200\231s disease have not been reported in heterozygotes. In the absence of marker analysis, screening should include a physical examination, liver bio- chemical tests , serum copper and caeruloplasmin levels, 24-hour urinary copper measurement, and careful s lit-lamp examination. CASE 47 321 Further reading Perri RE, Hahn SH, Ferber MJ (2005). Wilson Disease \200\223 keeping the bar for diagnosis raised. Hepatology; 42: 974. Roberts EA, Schilsky ML (2008). American Association for Study of Liver Diseases. Diagnosis and treatment of Wilson disease: an update. Hepatology; 47: 2089 \200\223111. Schilsky ML (2005). Wilson disease: new insights into pathogenesis, diagnosis, and future therapy. Curr Gastroenterol Rep; 7: 26 \200\22331. OXFORD CASE HISTORIES 322 Case 48 A 75-year-old retired truck driver was referred for evaluation of abnormal liver function t ests, which had been found at a routine check-up. He was asympto- matic. Prior medical hist ory included a myocardial infarction 4 years before, benign prostatic hypertrophy, and jaun dice at 17 years of age. He had never had a tattoo, drank very little, but had had blood tr ansfusions following a pros- tatectomy in 2001. He had not recently traveled and was a non- smoker. On examination, his pulse rate was 69bpm with frequent extrasystoles, and blood pressure wa s 145/80mmHg. He was apyrexial. There was no jaundice, pallor, lymphadenopathy, or oedema. Cardiovascular examination was unre- markable and his chest was clear. A liver edge was pal pable 8cm below the costal margin, but percussion indicated a liver span of 15cm, which is only slightly enlarged. The spleen was clearly palpable, but did not cross the mid- line. T here were no signs of chronic liver disease or portal hypertension. Investigations showed: 9/L, platelets 96 x 109/L Hb 13.4g/dL, WCC 7.66 x 10 INR 1.2 mol/L ALT 78 IU/L, ALP 1269 IU/L, GGT 1017 IU/L, Bilirubin 22 albumin 36g/L Blood movie: platelets reduced on movie. No platelet clumps seen. Howell \200\223Jolly bodi es seen. Ultrasound of the abdomen: the liver was diffusely heterogeneous and coarse in texture. The portal venous flows were normal. There was marked splenomegaly and the spleen had a bipola r length of 18cm. It, like the liver, had a very coarse, heterogeneous internal architectur e. Questions 48a) Discuss the differential diagnosis in this patient. 48b) What are Howell \200\223Jolly bodies and why are they significant? 48c) What further investigations would you plan? 48d) Discuss this condition. This page intentionally left blank OXFORD CASE HISTORIES 324 Answers 48a) What is the differential diagnosis in this patient? Splenomegaly may be caused by congestion, infiltration, immune acti- vation or expansion of haematopoietic cell lines and reticuloendothelial cells within the organ. Clinical examina tion should include a search for chronic liver disease with portal hypertension (congestive splenomegaly), signs of haemolysis and anemia (extramedullary haematopoiesis and expansion of reticuloendothelial cells), signs of chronic inflammatory disease or infections (immune activation), and signs of hematological malignancy (such as lymphoma or leukemia) or any o ther infiltrative condition (such as amyloid). Hepatomegaly associated with splenomeg- aly may result from liver disease causing portal hypertension, extramed- ullary haematopoiesis, or infiltration by the same condition. The presence of a high ALP with a raised GT suggests hepatic infiltra- tion. Our patient ha d no signs of haemolysis and was not anemic. There was no evidence of chronic liver disease or portal hypertension, nor was there any sign of a chronic inflammatory disorder. Malignant infiltration is likely, most commonly a lymphoma. Even though the patient had no peripheral lymphadenopathy, axial lymph nodes may be present and would favor Hodgkin \200 \231s disease. Leukemia and myeloproliferative conditions may also enlarge liver and spleen . Primary angiosarcoma may originate in the spleen or metastasize from the liver to the spl een. Other solid tumors rarely metastasize to the spleen, but melanoma can (and does!). The re was no evidence of previ- ous or concurrent melanoma in or patient. Non-malignant infiltration may result from extracellular depositions such as amyloidosis, s arcoidosis, or tuberculosis (associated with immune hyperplasia). Lipid storage diseases (e .g. Gaucher \200\231s disease) will not present at this age. Our patient had a very, but not \200\230massively \200\231, enlarged spleen. Massive enlar gement is defined as a spleen palpable >8cm below the costal margin. Some consider a spleen that crosses the midline as massively enlarged. Massive enlargement is caused by non-Hodgk in \200\231s lymphoma, chronic myeloid leukemia, chronic lymphatic leukemia, hairy cell leu kemia, myelofibrosis, and sarcoidosis. 48b) What are Howell \200\223Jolly bodies and why are they significant? Howell \200\223Jolly bodies are remnants of the nucleus of red blood cells from their immat ure stages, which are then detected in mature erythrocytes on CASE 48 325 a peripheral blood movie. Such remnants are usually removed by the spleen, so the presence of Howell \200\223Jolly bodies implies either absence of the spleen (e.g. splenectomy) or f unctional hyposplenism. Our patient clearly has a spleen that does not function. Diseases t hat are associated with impaired splenic function with an intact spleen include coeliac dis - ease, sickle cell disease (splenic infarction), systemic lupus erythematosis, rheumatoid arthritis, Grave \200\231s disease, Sj gren \200\231s syndrome, chronic liver disease, alc oholism, inflammatory bowel disease, and Whipple \200\231s disease. Amyloidosis and sarcoid osis may also cause functional hyposplenism. As a marker of hyposplenism, Howell \200\223Jolly bodies are insensitive, but specific. The y do not occur in mild hyposplenism. Their presence implies a level of functional hyposplen ism thought to put the patient at risk of overwhelming postsplenectomy infection. Such infe ctions are often cryptic with a short prodrome. Encapsulated organisms are usually responsi ble (Streptococcus pneumoniae, Haemophylus influenzae, or Neisseria meningitidis). Massive bacteraemia causes septic shock and dis- seminated intravascular coagulation. The mortality is up to 80% and death may occur within 24 \200\22348 hours. 48c) What further investigation would you plan in this patient? A CT scan of the chest, abdomen, and pelvis would identify any lymph- adenopathy in the che st or abdomen, a primary malignancy, or metastases. Tissue is needed to make a diagnosis. B ecause the liver is affected, a liver biopsy is appropriate, although a lymph node biopsy, bone marrow examination, or even a diagnostic splenectomy may be required. CT of chest and abdomen: the liver has an expanded, rounded and heterogeneous appearance, m easuring 14.5 x 10cm on axial section. The prostate is enlarged to 62mm diameter. There are degenerative changes of the spine. There is no suspicious bone lesion, and the lungs clear . The kidneys, adrenals, and pancreas are all normal. There is no gross lymphadenopathy, al though there are some small mesenteric nodes and general streaking of the intra-abdominal f at (Fig. 48.1). Liver biopsy shows angiosarcoma (Fig. 48.2 in central color section). 48d) Discuss this condition Angiosarcoma is a rare vascular tumor, accounting for 2% of all pri- mary liver tumors. Pri mary angiosarcoma of the liver has a strong male predominance, with a 4:1 ratio of males to females. Individuals are usu- ally > 60 years of age. Metastases to the lung, spleen and b ones may occur OXFORD CASE HISTORIES 326 Fig. 48.1 CT scan showing enlargement of liver and spleen, with a heterogenous parynchymal appearance in both organs. in descending order of frequency. It is strongly associated with environ- mental or occupat ional exposure to carcinogens, including colloidal thorium dioxide, arsenic compounds, poly vinyl chloride, inorganic copper, radiation exposure, and anabolic steroids. A history of e xposure is not commonly identified, however, as was the case with our patient. Nevertheless , because of the implications it is important that the patient is asked carefully about all their jobs and recreational activities. Fig. 48.2 (see color plate 26) Angiosarcoma of the liver. Vascular channels are identifiabl e (arrow), but not the characteristic spindle-shaped cells at this magnification. CASE 48 327 An angiosarcoma shows areas of necrosis and hemorrhage with one of four different growth pa tterns: multiple nodules, a large dominant mass, a mixture of these, or (unusually) a diffu se infiltrating tumor, which was the case in our patient. Histopathology shows spindle-shap ed cells, which may form vascular channels and are positive for vascular endothelial cell m arkers (CD31 and CD34) on immunohistochemistry (Fig. 48.2). No effective therapy exists. Neither excision of a localized tumor nor chemotherapy alters the outcome. Cases of angiosarcoma diagnosed incidentally on liver transplantation for anot her indication show rapid recurrence and have a poor prognosis. Liver transplantation is th erefore contraindicated. Survival from the time of diagnosis is <1 year in most instances, regardless of therapy. Management is palliative. Thorium dioxide (Thorotrast, Th232) was used worldwide as a radio- graphic contrast medium between 1928 and 1955, in a 25% colloidal solution. It is taken up by the reticuloendotheli al cells. Th232 is radioac- tive, emitting and particles and rays. It lingers in t he body and may be seen on CT scan 50 years after administration. It can be responsible for hyposplenism, bone marrow failure, and is associated with angiosar- coma of the liver. Our patient had neither a history of Thorotrast admin- istration, nor any sign of residual Tho rotrast on CT imaging. Exposure to arsenic comes from contamination of drinking water (India), burning of arsenic coal (China), or medicinal administration (Fowler \200\231s solution, used worldwide for ch ronic myeloid leukemia 1931 \200\2231953). The polymerization of vinyl chloride in the poly vinyl chlo- ride (PVC) industry since the mid 1930s lead to high levels of exposure among w orkers in the industry. The first case of angiosarcoma because of this occupational exposur e was identified in 1974. Since then tight controls on the work environment have been imple mented and cases caused by this exposure now occur rarely, if at all. Further reading Kim HR, Rha SY, Cheon SH et al. (2009). Clinical features and treatment outcomes of advanced stage primary hepatic angiosarcoma. Ann Oncol; 20: 780 \200\2237. Maluf D, Cottere ll A, Clark B et al. (2005). Hepatic angiosarcoma and liver transplantation: Case report and literature review. Transplant Proc; 37: 2195 \200\2239. Mu ller AF, Toghill PJ (1995). Hyposplenism in gastrointestinal disease. Gut 1995; 36: 165 \200\2237. Van Kampen RJW, Erdkamp FLG, Peters FPJ (2007). Thorium dioxide-related haemangiosarcoma of the liver. Neth J Med; 65: 279 \200\22382. OXFORD CASE HISTORIES 328 Case 49 A 49-year-old female carer developed severe abdominal pain over the course of a fortnight, with diarrhea, weight loss, and vomiting. She was admitted via the emergency department, wh ere a CT scan showed intestinal obstruction, a stenosing tumor in the transverse colon, and liver metastases. She was taken to theater, where an extended right hemicolectomy was perf ormed, with resection of a gangrenous loop of small bowel. This was complicated by an anast omotic leak requiring further laparotomy and ileostomy, following which there was wound deh iscence and discharge through two enterocutaneous fistulas. Seventeen days after the initia l admission, on a Friday, parenteral nutrition was requested urgently. On examination, the patient weighed 61kg, had lost 15kg in the previous 4 weeks, and had an output through the wound manager of 1650mL in the past 24 hours. Investigations showed: 9/L, platelets 100 x 109/L Hb 10.3g/L, WCC 9.4 x 10 mol/L, ALT 39 IU, ALP 157 IU Bilirubin 45 Albumin 20g/dL, phosphate 0.61mmol/L, magnesium 0.82mmol/L CRP >160mg/L. Questions 49a) Interpret the blood results. 49b) What are the dangers of starting parenteral nutrition immediately? 49c) What is the best advice? 49d) What is the optimal management strategy? This page intentionally left blank OXFORD CASE HISTORIES 330 Answers 49a) Interpret the blood results. This patient is dehydrated, evidenced by a disproportionate increase in urea compared with creatinine, in the context of a high stoma output (>1200ml/d) and high potassium (see Case 33). She is almost certainly septic given the low albumin (20g/dL). Sepsis is also consiste nt with the high CRP (>160mg/L). The anemia and hyperbilirubinaemia are most probably due t o haematoma formation and resorption after two major operations. The thrombocytopenia is li kely to be caused by bone marrow suppression from sepsis, which will also be contributing t o the anemia. Sepsis and hypovolaemia are therefore the key messages in this complex situat ion: both are surprisingly easy to overlook, because the patient is apyrexial and the stoma output is frequently not measured except on a specialist ward. 49b) What are the dangers of starting parenteral nutrition immediately? This patient is at risk of refeeding syndrome, which is defined as severe fluid and electro lyte shifts with related metabolic mayhem in malnour- ished patients undergoing refeeding ( see Case 37). The principal bio- chemical features of refeeding syndrome are hypophosphatae mia, hypomagnesaemia, hypokalaemia, glucose intolerance, fluid overload, and thiamine defic iency. Clinical consequences can include congestive heart failure, cardiac arrhythmias, ske letal muscle weakness, respiratory failure, metabolic acidosis, ataxia, seizures, encephalo pathy, and death. Patients at risk include those who have had: complete starvation for >7 days >20% loss of body weight in <3months catabolic state caused by sepsis. Because this patient has been referred on a Friday afternoon (as so often happens, when the urgency of the situation is recognized before the weekend!), there is greater risk of the clinical consequences of refeeding syndrome if feeding is started immediately, simply becau se monitoring over the weekend is often suboptimal. Designated central venous access for pa renteral nutrition is also a problem, unless insertion has already been organized, or if (i mprobably) the patient has an untouched central line port. Parenteral nutrition is never an emergency: the risk of death from refeeding exceeds the risk of delaying nutrition pending appropri- ate preparation. CASE 49 331 49c) What is the best advice? After explaining the dangers of starting intravenous nutrition immedi- ately and over the w eekend to the surgeons looking after her, the ward nurses, the patient, and her family, pre paration includes rehydration, electrolyte and vitamin replacement, with daily monitoring a ccording to refeeding guidelines below. This is enough to keep the team looking after the p atient occupied over the weekend, knowing that they are doing the best thing for the patien t. Electrolyte replacement: electrolytes need immediate replacement if the potassium is <2.5mm ol/L, magnesium <0.5mmol/L, or phosphate <0.3mmol/L. \200 .5mmol): intravenous potassium is always more Low potassium (<2 appropriate than oral potas sium pending parenteral nutrition. A care- fully monitored infusion pump should be used to administer 120mmol/L through a central line over 12 hours. Oral potassium usu- ally tastes disgusting. Remember that for the commonly prescribed Sando K, one tablet contains 12mmol, so 5 tablets/day (=60mmol) only meet (and do not exceed) ordinary daily requirements. .3mmol/L): intravenous Addiphos \204 20ml vial) Low phosphate (<0 in 500ml normal saline s hould be administered over 6 hours. Shake the bag well. One vial of Addiphos \204 contains phosphate 40mmol, potassium 30mmol, and sodium 30mmol. Oral phosphate causes diarrhea and should therefore be avoided. Low magnesium (<0 .5mmol/L): 50% magnesium sulfate 6g (=24mmol, or 12ml) in 500ml normal sa line should be given over 6 \200\22312 hours. The maximum infusion rate is 4mmol/hour of Mg . Oral magnesium causes diarrhea. : in practice, calcium is not too much of a problem. Low calcium If it is low, it is likely to be secondary to magnesium or phosphate deficiency; when these are replaced, the calcium usually returns to normal. If necessary, intravenous calcium gluconate can be given. In practice, any electrolyte concentration below the normal range (K <3.5mmol/L, P <0.6mmol /L, Mg <0.7mmol/L) merits proactive replacement during the weekend, or 48 hours before pare nteral nutrition is started. This is because the refeeding syndrome is characterized by fur ther electrolyte depletion, owing to intracellular shifts of electrolytes. Intravenous vitamins: thiamine is required. Pabrinex \204 1 pair of ampoules (= 250mg thia mine) should be given in 50 \200\223100ml normal saline over 30 minutes, daily for 3 days. OXFORD CASE HISTORIES 332 Insertion of a designated central venous line ONLY to be used for intravenous feeding: this can be done after the weekend, ideally as a peripherally inserted central catheter (PICC).