In our patient interface hepatitis and plasma cells were seen in the mononuclear portal cel lular infiltrate (see Figs 2.1 and 2.2 in the central color section). An international scoring system to aid in the diagnosis of autoimmune hepatitis has been de veloped as a research tool (Czaja 2006). This scoring system (Table 2.1) accommodates the d iverse manifestations of the disease and produces an aggregate score, reflecting the probab ility of the diagnosis. It may be used when the diagnosis of autoimmune hepatitis is in dou bt. OXFORD CASE HISTORIES 12 Fig. 2.1 (see color plate 1) A low-power magnification image of a liver biopsy, showing a s evere inflammatory infiltrate at the interface between the portal triad and lobule (arrow). Fig. 2.2 (see color plate 2) A higher magnification showing distinct plasma cells (arrow). Using the scoring system, this patient \200\231s aggregate score was 17 prior to ther- apy (female gender, ALP:ALT ratio <1.5, IgG >twice upper limit, antinuclear antigen >1/80, nega tive viral serology, interface hepatitis, and plasma cell infiltrate on liver histology). A pre-treatment score of >15 gives a definite diagnosis. 2e) How would you treat this patient? Treatment is with immunosuppression. The mainstay of treatment is corticosteroids. Azathiop rine may be added once liver function tests have normalized, often allowing the prednisolon e dose to be reduced to 5 \200\2237.5mg/day, or stopped completely. In our patient there wa s no CASE 2 13 Table 2.1 International scoring system for autoimmune hepatitis Criterion Component Score Criterion Component Score Sex Female +2 HLA DR3 or DR4 +1 AP:AST (or ALT) ratio > 3.0 \210\2222 Immune disease Thyroiditis, colitis, +2 others < 1.5 +2 Gamma-globulin or IgG level above normal > 2.0 +3 Other markers Anti-SLA/LP, actin, LC1, pANCA +2 1.5 \200\2232.0 +2 1.0 \200\2231.5 +1 < 1.0 0 ANA, SMA, or anti-LKM1 titres > 1:80 +3 Histological features Interface hepatitis +3 1:80 +2 Plasmacytic +1 1:40 +1 Rosettes +1 < 1:40 0 None of above \210\2225 Biliary changes \210\2223 Other features \210\2223 AMA Positive \210\2224 Treatment response Complete +2 Relapse +3 Viral markers Positive \210\2223 Negative +3 Drugs Yes \210\2224 Pre-treatment score No +1 Definite diagnosis: > 15 Probable diagnosis: 10 \200\22315 Alcohol < 25g/day +2 Post-treatment score > 60g/day \210\2222 Definite diagnosis: > 17 Probable diagnosis: 12 \200\22317 contraindication to azathioprine, so this was given in combination with prednisolone. Remis sion is defined as transaminases less than twice the upper limit of normal. Immunosuppressi on is usually required long term, but patients do not routinely require repeat liver biopsy . After withdrawal of therapy, only around 20% of patients have a sustained remission. Most relapses occur within 12 weeks of cessation of therapy and can be severe. However, relapse may occur months or years later, so there is a need for continued follow-up. Life expectan cy of treated patients exceeds 85% at 10 years and 74% at 20 years. In around 10% of patien ts, therapy fails to prevent progression of liver disease, with eventual hepatic decom- pen sation, leading to liver transplantation. OXFORD CASE HISTORIES 14 This patient responded well to treatment with corticosteroids and aza- thioprine, with norm alization of liver biochemistry, so she was maintained on immunosuppression. Alternatives e xist for those patients who do not tolerate first-line drugs. Mycophenolate mofetil and tac rolimus have both been used, although there are no controlled data. Further reading Czaja AJ (2007). Corticosteroids or not in severe acute or fulminant autoimmune hepatitis: therapeutic brinksmanship and the point beyond salvation. Liver Transpl; 13: 953 \200\2235. Czaja AJ (2006). Autoimmune hepatitis \200\223 approach to diagnosis. Med Gen Med; 8: 55. Juttner H-U, Ralls PW, Quint MF, Jenney JM (1982). Thickening of the gallbladder wall in acute hepatitis: Ultrasound presentation. Radiology; 142: 465 \200\2236. Montano Loza AJ, Czaja AJ (2007). Current therapy for autoimmune hepatitis. Nat Clin Pract Gastroenterol Hepatol; 4: 202 \200\22314. Heathcote J (2006). Treatment strategies for autoimmune hepatitis. Am J Gastroenterol; 101(Suppl. 12): S630 \200\2232. CASE 3 15 Case 3 A 35-year-old florist, 26 weeks pregnant, was referred to the outpatient department because of mild jaundice, a 1-month history of intense pruritus and fatigue. Her first pregnancy, 3 years previously, was complicated by hypertension, but was otherwise uneventful and the child remained healthy. The current pregnancy followed three miscarriag es. During this period, she was diagnosed with systemic lupus erythematosus (SLE) and antip hospholipid syndrome. There were no cerebral or renal manifestations of SLE. Current medica tions included azathioprine 200mg/day, prednisolone 5mg/day, low-dose aspirin, and low mole cular weight heparin. She had been on azathioprine for 2 years. On examination, she was fully orientated. Her pulse rate was 72bpm, and blood pressure 130/ 80mmHg. There was mild icterus, no spider naevi, no abdominal tenderness, and no hyper-refl exia. Investigations showed: 9/L, platelets 312 x 109/L Hb 12.5g/L, WCC 10 x 10 mol/L Na 135mmol/L, K 4.2mmol/L, urea 4.3mmol/L, creatinine 82 mol/L, AST 475 IU/L, ALT 157 IU/L, ALP 350 IU/L, Bilirubin 102 GGT 52 IU mol/L(normal 0 \200\22310) Serum bile acids 192 Urine dipstix \200\223 negative for protein. Questions 3a) What is the differential diagnosis? 3b) Is a liver biopsy necessary? 3c) What treatment should be instituted? 3d) What are the maternal and fetal prognoses? OXFORD CASE HISTORIES 16 Answers 3a What is the differential diagnosis? The differential diagnosis includes pregnancy-related liver disease and non-pregnancy relat ed liver disease, including complications of SLE. Pregnancy-related liver disease: Intrahepatic cholestasis of pregnancy Pre-eclampsia and eclampsia HELLP syndrome (Haemolysis (H), elevated liver enzymes (EL), low platelet count (LP) Acute fatty liver of pregnancy. Non-pregnancy related liver disease: Autoimmune hepatitis (see Case 2) Viral hepatitis (see Cases 16, 43, 44) Drug-induced hepatitis (see Case 1) Biliary obstruction (see Case 9) Primary biliary cirrhosis (see Case 4) Primary sclerosing cholangitis (see Case 50). The most likely pregnancy-related diagnosis is intrahepatic cholestasis of pregnancy. Pruri tus is the primary clinical symptom of intrahepatic cholestasis of pregnancy. The pruritus can range from mild and tolerable to severe and disabling. Pruritus is typically worse in t he evening, with a predilection for the palms or soles of the feet, and is not associated w ith any specific skin lesions. Mild jaundice occurs in 10 \200\22315% of cases, usually occ urring 1 \200\2234 weeks after the onset of the pruritus. The main biochemical alterations are elevations of serum bile acids, and transaminase concentra- tions. The serum concentrat ion of GGT may be modestly elevated. ALP is difficult to interpret during pregnancy, due to elevation of the placental isoenzyme. Diagnosis of intrahepatic cholestasis of pregnancy is one of exclusion. It is important to exclude other causes of liver disease and cholestasis. This case does not fit with the rare HELLP syndrome, because there is no evi- dence of haemolysis or thrombocytopenia, and the patient is relatively well. Patients with SLE are, however, at increased risk of pre-eclamp sia. Although there is hypertension, which raises the suspicion of pre-eclampsia, there is no proteinuria (making either pre-eclampsia or lupus nephritis most unlikely) or hyper-refl exia. Acute fatty liver of pregnancy is a CASE 3 17 sudden, catastrophic illness occurring almost exclusively in the third tri- mester, where m icrovesicular fatty infiltration results in encephalopathy and hepatic failure. The typical patient has 1 \200\2232 weeks of anorexia, nausea and vomiting, headache, and right upper quadrant pain; she looks ill, with jaundice, hypertension, oedema, ascites, a small liver, and hepatic encephalopathy. Non-pregnancy related causes of liver disease must always be consid- ered and autoimmune he patitis in particular, not least because this is more common in SLE. Autoimmune hepatitis w as sometimes (incor- rectly) called lupus hepatitis in the past, although it is a condition quite separate from SLE. Investigation should include screening for viral hepatitis, and radiologi- cal imaging of t he biliary tract for biliary obstruction due to gallstones, which are more common during pr egnancy. This can be done safely by abdominal ultrasound or magnetic resonance imaging. Dru g-induced liver disease is also important to consider. Although azathioprine can cause hepa titis, this is usually an acute event that occurs within 3 weeks of start- ing the drug and very rarely in patients who have been established on the drug for more than a month. There are anecdotes of azathioprine-induced nodular-regenerative hyperplasia, but these are exce ptional. Wide experi- ence of azathioprine in pregnancy for the treatment of many condition s (including inflammatory bowel disease) indicates that it is not only safe, with no increa se in miscarriage, still birth or congenital anomaly, but also that stopping the drug leads to a relapse of the underlying condition, which is more harmful to the fetus. 3b) Is a liver biopsy necessary? Liver biopsy is not ordinarily necessary for the diagnosis of intrahepatic cholestasis of p regnancy. Nevertheless, in this case, a biopsy was per- formed to exclude autoimmune hepati tis and the remote possibility azathioprine-induced liver damage. The biopsy was consistent with intrahepatic cholestasis of pregnancy, showing centrilobular cholestasis without infl ammation and cannalicular bile plugs among hepatocytes. Coexistent drug-induced hepatitis c ould not be excluded, but the con- siderations above (3a) made this unlikely. The important finding was that there were no features of autoimmune hepatitis, so she was treated as hav ing intrahepatic cholestasis of pregnancy. 3c) What treatment should be instituted? The primary objective of pharmacological treatment of intrahepatic cholestasis of pregnancy is to alleviate maternal symptoms and improve OXFORD CASE HISTORIES 18 fetal outcome. Currently, Ursodeoxycholic acid is the most effective treatment for intrahep atic cholestasis of pregnancy, and appears to work as a choleuretic, to promote the flow of bile (see Case 4). It is effective at alleviating pruritus and restoring bile acids toward s normal. Ursodeoxycholic acid is safer and more effective than cholestyramine, an anion-bi nding resin that is a bile acid sequestrant. Antihistamines are frequently used for treatin g pruritus, but it is their sedative effect that appears to relieve symptoms, rather than a ny effect on histamine produc- tion. Vitamin K should be administered regularly throughout pregnancy in patients with intrahepatic cholestasis of pregnancy, due to the increased risk of fetal hemorrhage and postpartum hemorrhage. Specialist advice is appropriate. 3d) What are the maternal and fetal prognoses? The maternal prognosis is good and symptoms resolve rapidly after delivery, accompanied by normalization of the liver function tests. There is a predispo- sition to post-partum hemor rhage, probably because of vitamin K deficiency related to cholestasis. Persistent cholesta sis after delivery should prompt reconsideration of other underlying liver disease, such as primary biliary cirrhosis, primary sclerosing cholangitis, or chronic hepatitis C, which m ay all cause pruritus during late pregnancy. Intrahepatic cholestasis of preg- nancy recurs during subsequent pregnancies in 45 \200\22370%. There are, however, significant risks to the fetus. Intrahepatic cholestasis of pregnancy i ncreases the risk of preterm delivery, meconium staining of amniotic fluid, fetal bradycard ia, fetal distress, and fetal loss. Most fetal death occurs after 37 weeks of gestation, so there is general agreement that all women with intrahepatic cholestasis of pregnancy shoul d be delivered no later than 37 \200\22338 weeks of gestation. Delivery prior to 36 weeks s hould be considered for severe cases with jaundice, progressive elevation in serum bile aci ds, and suspected fetal distress. In terms of the SLE, there is an increased risk of sponta neous abortion (note that this patient had three miscarriages prior to this pregnancy), int rauterine fetal death, intrauterine growth retardation, and preterm birth. This patient was delivered at 31 weeks because of increasing pruritus and slowing fetal gro wth. Her itching and liver function tests improved immediately post-partum, but did not com pletely normalize. The azathi- oprine was subsequently stopped with normalization of liver blood tests. Although the patient had been on azathioprine for over 2 years, the final diag nosis was felt to be a combination of intrahepatic cholestasis of pregnancy and azathioprin e-induced hepatotoxicity. CASE 3 19 Further reading Saleh M, Abdo K (2007). Intrahepatic cholestasis of pregnancy: review of the literature and evaluation of current evidence. J Womens Health; 16: 833 \200\22341. Pusl T, Beuers U (2007). Intrahepatic cholestasis of pregnancy. Orphanet J Rare Dis; 2: 26. Hay E (2008). Liver disease in pregnancy. Hepatology; 47: 1067 \200\22376. Gisbert JP, Gon z lez-Lama Y, Mat J (2007). Thiopurine-induced liver injury in patients with inflammatory bowel disease: a systematic review. Am J Gastroenterol; 102: 1518 \200 \22327. OXFORD CASE HISTORIES 20 Case 4 A 60-year-old woman, originally from Belgium was first seen in 1987 with asymptomatic abnor mal liver blood tests. Investigations at the time showed: 9/L, platelets 233 x 109/L Hb 12g/dL, WCC 4.0 x 10 mol/L, ALP 516 IU/L, GGT 217 IU/L, AST 42 IU/L, albu- Bilirubin 7 min 42g/L Ultrasound of the abdomen: normal. The patient had a history of treated hypothyroidism. She had been well until 2005, when she had been admitted for a single episode of haematem- esis and had undergone a gastroscopy. This showed her to have small oesophageal varices, with no signs of recent or imminent hemo rrhage. They were too small for therapeutic intervention. She had recently suffered a fall and had fractured her right humerus. She was now com- plaining of general fatigue and itchi ng, especially at night, localized to her forearms. Further investigations showed: 9/L Platelets 117 x 10 mol/L, ALT 139 IU/L, ALP 1173 IU/L, albumin 37g/L. Bilirubin 28 Questions 4a) What is the likely diagnosis and how was it confirmed? 4b) What is the significance of the humeral fracture? 4c) What is the significance of the portal hypertension? 4d) How would you treat the disease? 4e) How would you manage the patient \200\231s symptoms? This page intentionally left blank OXFORD CASE HISTORIES 22 Answers 4a) What is the likely diagnosis and how was it confirmed? The clinical picture is of progressive cholestatic liver disease with the development of po rtal hypertension, fatigue and itching. The differential diagnosis of asymptomatic cholesta tic liver function tests at presentation is intrahepatic biliary disease such as primary bi liary cirrhosis and primary sclerosing cholangitis. Other causes of a high alkaline phosphatase (ALP) include hepatic infil- tration (e.g. sarc oidosis, granulomatous hepatitis, hepatic metastases, amyloid, see Case 42). It is importan t to remember that the ALP also rises with chronic heart failure and active systemic connec tive tissue disease. Primary biliary cirrhosis is (by far) the most likely diagnosis, becau se she is female, has no history of colitis (as might occur with primary sclerosing cholang itis due to association with colitis, see Case 50), and has a history of autoimmune disease (hypothyroidism). Antimitochondrial antibod- ies (AMA) are positive in 90% of patients wit h primary biliary cirrhosis, being highly sensitive and specific. Whether antimitochondrial antibodies are involved in the pathogenesis of primary biliary cirrhosis, or merely an epi phenomenon, is unclear. If they are involved in the pathogenesis, it is difficult to explai n why bile ducts should be targeted, since mitochondria are present in most nucleated cells . Patients with primary biliary cirrhosis may also have a raised total IgM and may have ele vated total cholesterol. The role of liver biopsy in making the diagnosis of primary biliar y cir- rhosis is often debated, because the biliary disease is often patchy and the degree of fibrosis can be under-staged histologically. This woman was AMA positive and had liver f ibrosis stage 3/4 on biopsy of the liver. Primary biliary cirrhosis is a chronic autoimmune disease that leads to slowly progressive destruction and loss of small intralobular bile ducts, with resulting cholestasis, liver in jury, inflammation, and necrosis. This leads to fibrosis and ultimately to cirrhosis. The d esignation as primary biliary cirrhosis is a misnomer, since patients only have cirrhosis n ear the end of the disease course. A more accurate description is chronic non-suppurative d estructive cholangitis, but there is little chance that this catchy designation will replac e PBC! Primary biliary cirrhosis is found predominantly in females, with a female to male r atio of 8:1. The peak incidence is in the fifth decade of life and the disease is uncommon in patients younger than 25 years. The prevalence in women in the UK is 940 cases per milli on. It is thought that environmental factors, including toxins, viruses, or bacteria may pr ecipitate an autoimmune reaction in a genetically susceptible host. CASE 4 23 A genetic predisposition is suggested, because primary biliary cirrhosis is more common in first-degree relatives. No single infectious agent has been reproducibly detected in the li vers of patients with primary biliary cirrhosis, but candidates have included Escherichia c oli, Chlamydia pneumoniae, Helicobacter pylori, Mycobacterium gordonae, Novosphingobium aro maticiv- orans, and human -retrovirus. Appendectomy and tonsillectomy seem to have been p erformed more commonly in patients with primary biliary cirrhosis, but how this might predi spose to the disease is unclear. Patients may present clinically with symptoms of fatigue and pruritus, which often dominate the course of the disease. However, more than half of newly diagnosed patients will be asy mptomatic. This probably repre- sents the investigation of incidentally detected abnormal l iver function tests, or elevated serum cholesterol. Primary biliary cirrhosis may also be f ound on further investigation of a substantial list of other associated con- ditions. The s trongest disease association is with scleroderma, but others include Sj gren \200\231s syn drome, Raynaud \200\231s phenomenon, systemic lupus erythematosus, rheumatoid arthritis, pe rnicious anemia, type I diabetes, Addison \200\231s disease, autoimmune thyroid disease, co eliac disease, and inflammatory bowel disease, to name a few. In early primary biliary cirrhosis with or without symptoms, physical examination may be no rmal. Xanthelasma are rarely seen. Patients may have scratch-marks of pruritus. Signs and s ymptoms of associated diseases may be present. As the disease progresses with the developme nt of portal hypertension, splenomegaly may develop and collateral vessels found. Jaundice is a late finding in primary biliary cirrhosis and may not occur until the last 2 \200\2233 years of life. Referral for liver transplantation is consid- ered when the bilirubin rises to >100 mol/L. Variceal bleeding or increas- ing jaundice are often the first signs of pr ogressive liver disease. The 10-year survival in asymptomatic patients varies from about 60 % to 90%. The most common cause of death is liver failure. 4b) What is the significance of the humerus fracture? Primary biliary cirrhosis is associated with osteoporosis and a small, but significant incr ease in the risk of sustaining a fracture. Cirrhosis itself is also associated with an incr eased risk of fracture. About 20% of patients with primary biliary cirrhosis and endstage l iver disease will have osteopo- rosis. Management includes the modification of general risk factors for osteoporosis, including the avoidance of alcohol excess, smoking cessation and steroid therapy. Our patient had already had one fragility fracture from minimal trauma an d had a bone mineral density in the osteoporotic range (T-score < \200\2232.5). Treatment i s with bisphosphonates, OXFORD CASE HISTORIES 24 which are well tolerated and appear to be safe in the presence of small varices. All patien ts with cirrhosis or a sustained bilirubin more than 3 times the upper limit of normal had best receive calcium 1000mg and Vitamin D3 800 IU per day, regardless of bone mineral densi ty, because a fracture can be associated with decompensation of liver disease as a conseque nce of analgesics or anesthetics. 4c) What is the significance of the portal hypertension? Portal hypertension in primary biliary cirrhosis develops in the pre- cirrhotic stage becau se of fibrosis around the portal tracts. The presence of oesophageal varices implies portal hypertension with collateral circula- tion. Patients with primary biliary cirrhosis who ha ve blood platelets <200 x 109/L, albumin <40g/L and a bilirubin of >20 mol/L should be scr eened for oesophageal varices. Our patient has small varices, and annual follow-up endoscop y was arranged. Once varices enlarge to 50% of the lumen, primary therapy to reduce portal hypertension with non-selective beta-blockers or prophylactic endoscopic banding appears to reduce the risk of an index variceal bleed (see Case 5). 4d) How would you treat the disease? The only therapy thought to have any effect on the progression of disease is ursodeoxycholi c acid. Ursodeoxycholic acid is a bile acid that reduces cholestasis (see Cases 3 and 50). It occurs naturally in humans as a small proportion of the bile acid pool (2%). The optimal dose is thought to be 13 \200\22315mg/kg/day, so that it becomes the dominant bile acid in the bile acid pool. It enhances endogenous secretion (choleuretic effect), is less cyto- t oxic than other bile acids, and is associated with less cytokine expression as well as a re duction in aberrant HLA expression by biliary endothelium. It is clinically associated with improvement in liver enzyme tests, with an initial response evident at 6 weeks. The rapid initial response slows to a steady subsequent improvement. Within 2 years 20% will have nor mal liver enzymes, which increases to 35% at 5 years. Early histological stages (I and II) may have slower progression on ursodeoxycholic acid, but a significant survival benefit has not yet been shown. The indication for treatment with ursodeoxycholic acid is a positive antimitochondrial anti body with abnormal liver enzymes. Ursodeoxycholic acid may interact with clofibrate and col estyramine, so should be taken 4 hours apart from these medications. Clinical trials of oth er drugs have found no benefit in primary biliary cirrhosis, including colchicine, methotre xate, penicillamine, azathioprine or cyclosporin, either alone or in combination with ursod eoxycholic acid. Despite the use of CASE 4 25 ursodeoxycholic acid, progression to liver transplantation still occurs in a minority. Prim ary biliary cirrhosis recurs in the graft organ in 20%, but progression is slow, seldom lea ding to retransplantation. Associated con- ditions need treatment independently of the prim ary biliary cirrhosis. 4e) How would you manage the patient \200\231s symptoms? Pruritus and fatigue are common and often debilitating symptoms. Both are poorly understood and benefit of therapy is often difficult to measure objectively. Eighty percent of patien ts with primary biliary cirrhosis have pruritus at some stage. Pruritus occurs in cholestasis of any cause and may be the first manifes- tation of primary biliary cirrhosis before diagnosis. It is alleviated by sun- light and ultraviolet light a nd may yet improve as liver disease progresses. Bile acids are thought to be directly pruri togenic although opinions differ. For this reason, the bile acid sequestrant, colestyramine , is used as first- line therapy. Note the potential interaction with ursodeoxycholic acid (above). It is safe at a dose of 4 \200\22312g/day, but is unpalatable, poorly toler- ated due to gastrointestinal symptoms, and the evidence for efficacy in pruritus is scant. It sh ould be taken at the time that the gallbladder emp- ties at meal times and the dose can be divided, half before and half after breakfast. For those who cannot tolerate colestyramine, the bile acid sequestrant colesevalam is available in capsule form, but is still undergo- ing clinical trials in pruritus. In addition to the pruritogenic effect of bile acids, chol estasis is thought to be associated with an increase in endoge- nous opioids. Opioid antago nists may reduce the central neurotransmis- sion of pruritic signals. Opioid withdrawal, ac ute pain, the development of a pain syndrome, and hepatotoxicity may occur with opioid anta gonists. Naltrexone has been shown to have a clear benefit in relieving pruritus. Rifampici n, which appears to act by reducing transfer of bile acids across the hepatocytes, has also been shown to relieve pruritus. Sertraline has been tried and exposure to ultraviolet ligh t may help, keeping in mind the risks of overexposure. Ultimately intractable pruritus may only be successfully treated with liver transplantation. Fatigue is a troublesome symptom to treat and a well-recognized fea- ture of cholestatic li ver disease. Fatigue in primary biliary cirrhosis does not correlate with severity or durat ion of disease, pruritus, liver function impairment, age, thyroid status, or mental acuity, but does correlate with autonomic dysfunction, sleep disorders, and depression. Fatigue is thought to be centrally mediated. Postulated mechanisms include the reaction to the diagno sis of primary biliary cirrhosis (although fatigue often precedes OXFORD CASE HISTORIES 26 the diagnosis), a cytokine effect, excessive manganese, and altered func- tion of the hypot halamic-pituitary-adrenal axis. It is of fundamental importance to exclude other, treatable causes of fatigue that may be asso- ciated with primary biliary cirrhosis, including Addis on \200\231s disease, coeliac disease, or hypothyroidism. Trials with the 5-hydroxitryptami ne 3 (5 HT3) receptor antagonist, ondansetron to alter serotonergic neu- rotransmission, ha ve shown no benefit. Daytime somnolence may be helped by modafenil, a stimulant used in nar colepsy. Further reading Kumagi T, Heathcote EJ (2008). Primary biliary cirrhosis. Orphanet J Rare Dis; 3: 1. Mayo M J (2008). Natural history of primary biliary cirrhosis. Clin Liver Dis; 12: 277 \200\22388. Lindor K (2007). Ursodeoxycholic acid for the treatment of primary biliary cirrhosis. N Engl J Med; 357: 1524 \200\2239. Tandon P, Rowe BH, Vandermeer B, Bain VG (2007). The efficacy and safety of bile-acid binding agents, opioid antagonists, or rifampin in the treatment of cholestasis-associated pruritis. Am J Gastroenterol; 102: 1528 \200\22336. CASE 5 27 Case 5 A 52-year-old retired army major presented with recurrent haematemesis and melaena. The pat ient had been previously diagnosed with liver cirrhosis, secondary to alcohol abuse. He had had two episodes of variceal hemorrhage 2 years previously, which had been controlled by o esophageal variceal band- ing. He continued to drink up to six standard alcoholic drinks pe r day. He had type 2 diabetes, for which he was taking metformin 500mg twice daily. He was also taking spironolactone 50mg/day. On examination, he was very unwell with a pulse rate of 110bpm, blood pressure 95/55mmHg, o xygen saturation 95%, and temperature 35.8 C. There were multiple spider naevi, but no jau ndice or ascites. The patient was not confused and there was no asterixis. Investigations showed: 9/L, platelets 83 x 109/L Hb 11.4g/dL, WCC 7.1 x 10 Prothrombin time: 15.3 sec mol/L Na 134mmol/L, K 4.8mmol/L, urea 11.0mmol/L, creatinine 104 Glucose 24.2mmol/L mol/L, ALT 75 IU/L, ALP 100 IU/L, GGT 320 IU/L, Bilirubin 35 albumin 32g/L Gastroscopy showed four oesophageal varices protruding half way across the lumen. Seven var iceal bands were applied with a good result. Questions 5a) How would you manage this patient prior to endoscopy and what initial therapy would you introduce following endoscopy? 5b) What are the predictors of failure to control variceal bleeding? Unfortunately, the patient did re-bleed and required another endoscopy, but the endoscopist was unable to control the bleeding. By this stage the patient had had 10 units of red pack ed cells and remained tachycardic and hypotensive. 5c) What management should be considered at this stage? 5d) Why did the patient became confused and disorientated several days later? 5e) What is the subsequent management plan for patients in whom acute variceal bleeding is controlled endoscopically? OXFORD CASE HISTORIES 28 Answers 5a) How would you manage this patient prior to endoscopy and what initial therapy would you introduce following endoscopy? The immediate management includes: Correct hypovolaemia Prophylactic antibiotics Vasoactive drugs Endoscopic therapy Treat and prevent encephalopathy. Correct hypovolaemia \200\230Cautious and conservative \200\231 blood volume restitution is currently recom- me nded, using packed red blood cells to maintain the hemoglobin at approximately 7 \200\2239g /dL, and intravenous colloid to maintain haemody- namic stability. Crystalloid, including s aline, can be given in an emergency but continuous saline infusion should be avoided, becau se this will pre- cipitate ascites and peripheral oedema. Monitoring central venous pres- s ure helps avoid hypovolaemia, which is a common cause of renal failure in such patients. On the other hand, over transfusion should also be avoided, because volume overload increases portal pressure, which can precipitate further bleeding. Although cirrhotic patients with gastrointestinal bleeding often have a coagulopathy, there is no evidence that fresh frozen plasma or platelet administration is helpful, and there is some evidence that it is harmfu l due to volume expansion. Prophylactic antibiotics The use of prophylactic antibiotics (oral quinolone or intravenous ceftri- axone) should be standard therapy for patients with cirrhosis who have variceal bleeding. and should be ins tituted from admission and continued for approximately 5 days. An association with bacteria l infection and variceal bleeding has been shown in randomized trials. Antibiotics decrease the rate of bacterial infections including spontaneous bacterial peritonitis, decrease the incidence of early re-bleeding, and significantly improve survival. Vasoactive drugs In suspected variceal bleeding, vasoactive drugs (such as terlipressin) should be started a s soon as possible, before diagnostic endoscopy. CASE 5 29 Vasopressin and its analogs, such as terlipressin, cause splanchnic vasoconstriction, leadi ng to a reduction in portal pressure. Randomized controlled trials have shown that early ad ministration of vasoactive drugs reduces the rate of active bleeding, facilitates diagnosti c and therapeutic endoscopy, improves the control of bleeding and may decrease bleeding- re lated mortality. Vasoactive drug therapy should be administered for about 5 days, because t his is the period in which early re-bleeding is most frequent. Several drugs are available to treat acute variceal hemorrhage; the choice depends on local availability, bearing in mind that the only drug shown to improve survival is terlipressin . Somatostatin and octreotide have a similar effect on bleeding, but have not been shown to improve survival. Randomized controlled trials have shown that the efficacy of vasoactive therapy is significantly improved when combined with endo- scopic therapy. If vasoactive dr ugs are started as soon as possible before endoscopy, the incidence of active variceal blee ding during the endoscopy decreases from 50% (when drugs are not used), to 20 \200\22325%. Terlipressin and octreotride have fewer systemic side effects, such as angina or gut ischae mia, than vasopressin, but should still be used with caution in people with a history of co ronary artery disease. Endoscopic therapy Endoscopy should be performed as soon as possible after resuscitation, especially in patien ts with active bleeding and features suggesting cirrhosis. The aim is to stop bleeding by b anding (ligation) or sclerotherapy, and subsequently to obliterate the oesophageal varices. Variceal wall tension is the key factor that determines variceal rupture. Endoscopic thera py reduces variceal wall tension by reducing variceal size until obliteration, and by incre asing the thickness of the vascular wall. Variceal banding has proved more effective and sa fer than sclerotherapy (with eth- anolamine) and is currently the endoscopic treatment of c hoice for oesophageal varices. Nevertheless, the choice is also influenced by the availabil ity of equipment and expertise. Variceal obturation with tissue adhesives such as cyanoacry late or with thrombin are generally limited to the treatment of gastric varices. The current recommended therapy for variceal bleeding (combining vasoactive drugs, emergenc y endoscopic variceal banding and antibiotic prophylaxis), has reduced 5-day re-bleeding ra tes from 30% to 10 \200\22315%. Endotracheal intubation may be required for airway protecti on during endoscopy, particularly in patients with encephalopathy. OXFORD CASE HISTORIES 30 Treat and prevent encephalopathy Hepatic encephalopathy can be precipitated by bleeding in patients with cirrhosis. Patients who present or develop encephalopathy should be treated with lactulose. Although there are no studies to evaluate the value of lactulose for preventing hepatic encephalopathy, eithe r lactulose or phosphate enemas are usually given to prevent encephalopathy following a var iceal bleed. Following endoscopy a proton pump inhibitor should be given, because acid suppression has b een shown to reduce the risk of bleeding from oesophageal ulcers following variceal banding . Proton pump inhibitors should be continued until varices have been eradicated. A non-sele ctive beta-blocker should also be started (below). 5b) What are the predictors of failure to control variceal bleeding? Clinical factors associated with failure to control bleeding and mortal- ity are: Active bleeding at endoscopy Shock at admission Early re-bleeding (<5 days) Severity of liver disease (Child \200\223Pugh grade: mortality in patients with Class C = 7 0 \200\22380%) Raised bilirubin Prothrombin time (reflecting severity of liver disease) Thrombocytopenia (indirect measure of portal hypertension) Encephalopathy Recent use of corticosteroids for alcoholic hepatitis within 7 days of bleeding Age >60 years Complicating hepatocellular carcinoma. Portal hypertension increases with increasing severity of cirrhosis. The best predictor of re-bleeding is, however, an increased hepatic venous pressure gradient. The hepatic venous pressure gradient is a measure of the severity of portal hypertension. A hepatic venous pre ssure gradient >20mmHg has been shown to be independently associated with mortality and ear ly re-bleeding. Measurement of hepatic venous pressure gradient is performed by transjugula r venous cannulation, and requires access to skilled interventional radiology. Although acc urate and reproducible, CASE 5 31 with a low coefficient of variation in measurement and few complica- tions, it is rarely us ed outside the research setting except in one or two centers. Unfortunately, the patient did re-bleed and required another endos- copy, but the endoscopi st was unable to control the bleeding. By this stage the patient had had 10 units of packed red cells and remained tachycardic and hypotensive. 5c) What management should be considered at this stage? This patient has uncontrolled variceal bleeding despite medical and endo- scopic therapy. S uch patients are best managed with a transjugular intra- hepatic portal systemic shunt (TIP SS) (Figs 5.1a and 5.1b). TIPSS is an interventional treatment to decompress the portal sys tem by creation of an intrahepatic shunt between the portal and hepatic veins. TIPSS is onl y indicated for \200\230salvage therapy \200\231 when first-line methods (medical and endo scopic) have failed. Studies report immediate control of bleeding in 91 \200\223100% of cas es, 30-day re-bleeding in 7 \200\22330% and a 1-month mortality of 28 \200\22355%, reflecti ng the severity of the underlying liver disease . If access to TIPSS is not immediately available, mechanical balloon tam- ponade is accepted as a temporary measure until definitive therapy can be instituted. Most commonly used is t he three-lumen, double balloon Sengstaken-Blakemore tube. Only the gastric balloon need be used (filled with about 250ml of water mixed with 50ml radiological contrast) in most cases . Insertion is best achieved using a well lubricated stiffening guidewire, and should be ca rried out by an experienced physician, because of the risk of oesophageal perforation. The oesophageal balloon is rarely necessary and should not be insufflated for more than 8 hours . Surgical shunting, (portocaval or splenorenal) does not appear to improve survival, and is associated with a substantial incidence of enceph- alopathy. Surgery should only ever be co nsidered in patients with non- severe (Child \200\223Pugh A) liver disease. Liver transplan tation is not indicated for an acute bleeding episode, but all such people should be consid ered as transplant candidates, if only to exclude this as an option if (for instance) the p erson continues to drink or has substantial comorbidity. 5d) Why did the patient became confused and disorientated several days later? The most likely explanation for the confusion in this patient is post-TIPSS hepatic encepha lopathy. Hepatic encephalopathy is the main complication that has limited the application o f TIPSS. Clinically evident hepatic encephalopathy develops in approximately 35% of patient s after TIPSS, most often within the first 7 days. It is often short lived when managed OXFORD CASE HISTORIES 32 Guidewire going via the hepatic veins through the liver Varices with collateral flow away from the portal vein Tip of self-expanding stent Fig. 5.1a This picture shows the wire through the hepatic vein into the portal vein, with m etal TIPSS stent visible. There are varices visible on the right. Expanded stent Metal coils Portal vein Fig. 5.1b This picture shows the metal TIPSS stent, which is just proximal to the opacified portal vein. The varices seen on the right have been coiled. with regular lactulose, but in severe cases the shunt has to be reduced in diameter or occl uded, with all the implications for increasing the hepatic venous pressure gradient and re- bleeding. Our patient responded well to treatment with lactulose. Interestingly, the develo pment of post-TIPSS encephalopathy is not associated with a poor prognosis, and minor degre es of hepatic encephalopathy are no more prevalent after TIPSS than expected in a general c irrhotic population. CASE 5 33 5e) What is the subsequent management plan for those patients in whom