222 Radiological and other GI procedures Abdominal ultrasound is used for the investigation of abdominal pain, abnormal LFT, jaundice, hepatomegaly, or abdominal masses. Patients should be NPO by mouth for 4 h before the scan to allow visualization of the gallbladder. Pelvic u ltrasound requires the bladder to be full. Ultrasound may also be used to guide diagnostic biopsy or therapeutic aspiration. Endoscopic retrograde cholangiopancreatography Diagnostic indica- tions: With the advent of MRCP (below), diagnostic ERCP is uncommonly performed. Indications to perform ERCP prior to MRCP are for therapeutic intervention or wh en clinical suspicion is high for therapeutic interven- tion. Indications for ERCP include cholangitis, jaundice with dilated intrahe- patic ducts, recurrent pancreatitis, symptomati c choledocholithiasis, biliary obstruction, biliary strictures. Preprocedure: Check clottin g and platelet count. NPO after midnight. Obtain informed consent. Sedation is accom- plish ed similarly to other endoscopic procedures. Procedure: A catheter is advanced from a side- viewing duodenoscope via the ampulla into the common bile duct and/or pancreatic duct. Cont rast medium is injected and x-rays taken to show lesions in the biliary tree and pancreatic ducts. Complications: Pancreatitis, bleeding, cholangitis, perforation. Mortality: <0.2% o verall; 0.4% if stone removal. Small bowel follow-through After bowel preparation, barium i s ingested and serial x-ray films are taken every 30 min until barium reaches the cecum. En hanced films are taken of areas of interest (e.g., terminal ileum). Small bowel enema After bowel preparation, barium is introduced via duodenal intubation. Although technically more demanding than a barium follow-through, this method results in better mucosal definition. Barium enema Always do a rectal exam first rigid sigmoidoscopy and biopsy. Preparation i s per colonoscopy (p. 222). For double-contrast bar- ium enema, barium and air are introduc ed per rectum. Special views may be needed to visualize the areas of interest. Gastrografin may be used instead of barium in suspected colonic obstruction. It may show diverticular d is- ease or cancers (e.g., an irregular \200\234apple-core \200\235 narrowing of the lumen ). In Crohn \200\231s disease, look for \200\234cobblestoning, \200\235 \200\234rose thor n \200\235 ulcers, colonic strictures with rectal sparing. Disadvantages: Significant radia tion dose; no biopsy possible. Computed tomography is indicated if ultrasound is technicall y difficult or nondiagnostic. It allows better visualization of retroperitoneal structures but requires skilled interpretation. Oral or IV contrast may be given to enhance definition . The main disadvantage is the high radiation dose. Magnetic resonance imaging provides sup erior soft tissue imaging and enables the distinction of benign and malignant lesions. The other advantage over CT is the lack of radiation. Disadvantages are that patients with pace - makers and certain metal implants cannot be scanned and that the scanner itself can induc e claustrophobia. Magnetic resonance cholangiopancreatography MRCP enables in vivo anatomic exploration of the main pancreatic duct. Horizontal sections provide helpful radioanatomic information. The tech- nique nevertheless remains limited by poor spatial resolution. MRCP had a sensitivity of 83% and a specificity of 99% for diagnosing common bile duct stones, and according to some authorities, is the investigation of choice \200\224 partly, no doubt , due to lack of side effects. Endoscopic ultrasound An ultrasound transducer is placed at the tip of an endoscope, allowing for unprecedented visualization of the GI tract and its a djacent structures. The layers of the GI tract can be discerned (allows for unprecedented e valuation of submucosal lesions) and adjacent organs (pancreas, mediastinal structures). A fine-needle aspiration (FNA) or core biopsy can be accomplished through the endoscope, allo wing for tissue acquisition. EUS has revolutionized cancer diagnosis and staging of esopha- geal, pancreaticobiliary, gastric, and colorectal cancers. Imaging via a wireless enterosc opy capsule This capsule is swallowed and sends images to a recorder worn by the patient. I t allows for visualiza- tion of the small bowel mucosa and is indicated for obscure GI blee ding, detection of inflammatory bowel disease (IBD), etc. Recently, it is approved y g o o r e t n e o r t s a G l 223 for evaluation of the esophagus as well. Robotic biopsy and therapeutic procedures are not yet possible. Deep bowel enteroscopy with double balloon, single balloon, or spiral enteros copy . An enteroscope (a long endoscope) and an added balloon-like device can be used in ta ndem to allow the scope to be inserted deep into the small bowel. The entire length of smal l bowel can be reached in most cases. The sequential advancement of balloon and scope allow s for plication and folding of the bowel to shorten the length and advance the scope furthe r. This technique is useful to reach the small bowel and provide diagnosis of small bowel d iseases such as lymphoma or Crohn \200\231s with ERCP in patients with Roux-en-Y gastric by pass or therapy for bleeding. It can also be used in retrograde fashion to advance a scope through the colon and into the distal ileum. Liver failure Definitions Acute liver failure may occur suddenly in the previously healthy liver, precipitating elevated INR ( \211 1.5), rapid deterioration of liver function, ons et of encephalopathy, or change in mental status] Acute hepatic failure is liver failure of <26 wks duration). Liver failure more commonly may occur as a result of decompensation of chronic liver disease; i.e., acute-on-chronic hepatic failure . Many terms are used, includ ing fulminant hepatic failure, which refers to severe acute liver injury with synthetic dys function and encephalopathy occurring within 8 wks of the onset of symptoms. Subfulminant h epatic failure refers to impaired synthetic function and encephalopathy occurring within 9 \200\22326 wks (<6 months). Immediately upon development of acute liver failure (<26 wks du ration): Elevated INR ( \211 1.5) and encephalopathy in a patient: Must initiate contact with a transplant center as early transfer essential. Causes Infections: Viral hepatitis, y ellow fever, leptospirosis. Drugs: Acetaminophen overdose, halothane, isoniazid. Toxins: Am anita phalloides mushrooms, carbon tetrachloride. Vascular: Budd \200\223Chiari syndrome, v eno-occlusive disease. Others: Primary biliary cirrhosis, hemochromatosis, autoimmune hepat itis, 1 -antitrypsin deficiency, Wilson \200\231s disease, fatty liver of pregnancy, mal ig- nancy, drug-induced liver disease. Clinical features Hepatic encephalopathy is graded a s follows: 224 Grade I Altered mood or behavioral changes, day-night reversal, hyperreflexia Increased drowsiness or hypersomnia, confusion, Grade II slurred speech, asterixis Grade III Stupor, incoherence, restlessness or severe agitation, clonus, arousable to vocal stimuli Grade IV Coma, decerebrate posturing. Patients determined to have encephalopathy should be trans- ferred to the icu . Intubate wh en reaches grade III to IV encephalopathy. Other features: Jaundice, fetor hepaticus (sweat has pungent smell), con- structional apraxia (ask the patient to draw a five-pointed star) . Signs of chronic liver disease suggest acute-on-chronic hepatic failure. Investigations Blood tests: inr/prothrombin time (pt), blood type and screen, CBC (infec- t ion, GI bleed); chemistry (renal failure); LFT (bilirubin, AST/ALT, and alk phos); pregnanc y test, hepatic synthetic function (albumin, bilirubin) amylase, lipase; glucose (hypoglyce mia), acetaminophen level, ethyl alcohol (ETOH) level, consider aspirin level if suspected overdose, hepatitis serolo- gies (anti-HAV IgM, HBsAg, anti-Hbc IgM, anti-HEV, anti-HCV, HC V RNA, HSV1 IgM, VZV, ferritin and iron studies, 1 -antitrypsin level, serum ceru- lopla smin level, amylase, lipase, antinuclear antibody (ANA), anti-smooth muscle antibodies (ASM A), immunoglobulin level, toxicology screen, ABG, arterial lactate, ammonia. Microbiology: Blood culture; urine culture; HIV-1, HIV-2; if ascites, then cell count/culture of ascites; ascitic neutrophils >250/mm 3 indicates sponta- neous bacterial peritonitis (SBP). Total a scitic white blood cells (WBCs) >500/mm 3 also indicates SBP. Radiology: CXR, abdominal ult rasound; Doppler flow studies of the portal vein and hepatic artery (and hepatic vein, in s uspected Budd \200\223Chiari). CT brain to exclude other causes of altered mental status Ne urophysiological studies: Electroencephalogram (EEG) may show diffuse high-voltage slow wav eforms. Management Beware of sepsis, hypoglycemia, and encephalopathy 4 : \212 y g o o r e t n e o r t s a G l Nursing care with a 20 \200\22330-degree head elevation in fulminant hepatic fail- ure to r educe intracranial pressure (ICP) and avoid aspiration. May also protect the airway by inse rting an nasogastric (NG) tube and removing any blood or other contents from stomach. Monit or temperature, pulse, respiratory rate (RR), BP, pupils (uncal her- niation due to \206 \221 ICP in fulminant hepatic failure), urine output hourly. Check CBC, chemistry, LFTs, an d INR daily. Give 10% dextrose IV, 1 L/12 h to avoid hypoglycemia. Give 50 mL 50% dextrose IV if blood glucose <60 mg/dL (perform every 1 \200\2234 h in acute liver failure). Treat t he cause, if known (e.g., acetaminophen poisoning [p. 790]). If malnourished, obtain nutrit ion help (e.g., diet rich in carbohydrate- and protein-derived calories, preferably orally; give thiamine and folate supplements as needed. Hemofiltration or hemodialysis, if renal f ailure develops (see Table 7.8). Avoid sedatives or other drugs with hepatic metabolism. Co mmunicate early with your nearest liver transplant center regarding the appropriateness of transfer (see Table 7.9). \212 \212 \212 225 \212 \212 \212 \212 \212 Prognosis Poor prognostic factors: Grade III or IV encephalopathy, age >40 yrs, albumin <3. 0 g/dL, drug-induced liver failure (see Table 7.10), sub- fulminant hepatic failure worse t han fulminant failure \200\224only 65% survival post-transplantation. 4 Lee W, Larson A, Stravitz, RT. AASLD Position Paper: The management of acute liver failur e: update 2011. Hepatology . 2005; 41:1179 \200\2231197. Table 7.8 Treating the complications of acute hepatic failure Bleeding: Vitamin K 10 mg/d IV at least 1 dose; platelets and/or FFP for active bleeding or procedures; PRBCs as needed; recombinant activated Factor VII for invasive procedures Infe ction: Until sensitivities are known, give ceftriaxone 1 \200\2232 g/24 h IV. Avoid gentami cin or other nephrotoxic meds (increases risk of renal failure). Ascites: Fluid restriction , low-sodium diet, diuretics, daily weights Hypoglycemia: Check blood glucose regularly and give 50 mL of 50% glucose IV if levels fall below 60 mg/dL. Monitor plasma K + . Encephalo pathy: Avoid sedatives; 20 \200\22330-degree head elevation in acute hepatic failure; lactu lose to alter the gut flora and thus reduce nitro- gen (ammonia) production. Aim for three soft stools a day; be careful with oral neomycin \200\224may worsen renal failure; consider oral rifaximin instead. Cerebral edema: Give mannitol IV bolus at 0.5 \200\2231.0 g/kg. Hy perventilation in times of impending herniation. Consider hypertonic saline, barbitu- rates , corticosteroids, or physician-induced hypothermia. Hepatorenal syndrome (HRS): On present ation, check volume status, most patients need fluid resuscitation to maintain adequate int ravas- cular volume. If BP fails to respond, then initiate norepinephrine in volume-refract ory hypotension. Vasopressin can be used as adjunct to norepinephrine refractory hypotensio n. Goal mean arterial pressure (MAP) >75, CPP 60 \200\22380. Protect renal function with ad equate BP, avoid nephrotoxins. If dialysis is needed, recommend continuous filtration. 226 Table 7.9 King \200\231s College Hospital (UK) criteria for liver transplantation Arterial pH <7.3 following fluid resus- citation, regardless of the stage of encephalopathy Or all of the following: INR >6.5 Creatinine >3.4 mg/dL Grade III or IV encephalopathy INR >6.5 Acetaminophen related fulmi- nant hepatic failure (FHF) Non \200\223acetaminophen-related FHF Or three out of five of the following: 3 >1 wk duration of jaundice prior to 1 Drug/toxin-induced liver failure, or indeterminate cause onset of encephalopathy 4 INR >3.5 5 Bilirubin >17 mg/dL 2 Age <10 or >40 In some centers, transplantation is either cadaveric or from live donors (e.g., right lobe) . y g o o r e t n e o r t s a G Table 7.10 Prescribing in liver failure l Avoid opiates and benzodiazepines if possible. Be careful with diuretics (increases risk of encephalopathy) and avoid oral hypoglycemic agents. Warfarin effects are enhanced, therefo re monitor the INR closely. Avoid IV saline solutions which are hypotonic. Hepatotoxic drug s include acetaminophen, methotrexate, phenothiazines, isoniazid, azathioprine, estrogen, 6 -mercaptopurine, salicylates, tetracycline, mitomycin, and sev- eral other antibiotics, ant ivirals, antifungals, antidepressants, etc. When in doubt, refer to the specific medication \200\231s package insert concerning potential adverse effects when prescribing a new medic ine. Cirrhosis Cirrhosis implies irreversible liver damage. Histologically, there is loss of nor mal hepatic architecture with fibrosis and nodular regeneration. Causes Chronic alcohol abu se, chronic viral hepatitis infections, primary biliary cirrhosis, hereditary hemochromatos is, and others: See Table 7.11. Presentation varies from asymptomatic with abnormal LFTs, t o dec- ompensated end-stage liver disease with all its associated complications. Chronic li ver disease: Leukonychia \200\224white nails without clear demarcation of the lunulae; Terr y nails \200\224white proximally, but distal 30% reddened with telangiectasias; hypoalbumin emia with ascites; palmar erythema (hyper- dynamic circulation); spider nevi or angiomas; D upuytren contracture (in alcoholic cirrhosis); gynecomastia; testicular atrophy; parotid gl and enlarge- ment; clubbing; hepatomegaly or shrunken/fibrotic liver in late disease. Compl ications Hepatic failure: Coagulopathy (low levels of factors II, VII, IX, and X cause elev ated INR); encephalopathy \200\224asterixis and confusion, coma; hypoalbuminemia (edema, le ukopenia, ascites); sepsis (spontaneous bacterial peritonitis); hypoglycemia; GI bleeding; renal failure. Portal hypertension: Ascites; splenomegaly; portosystemic shunts including e sophageal varices (frequently present as a life-threatening upper GI bleed) and \200\234ca put medusa \200\235 (enlarged superficial periumbilical veins). Increased risk of hepatocel lular carcinoma. Tests Blood: LFT: or ^ bilirubin, ^ AST, ^ ALT, ^ alk phos, and ^ -g lutamyl transpeptidase (GGT). Later, with loss of synthetic function, look for albu- min ^ PT/INR. Low WBC and platelets indicate hypersplenism. Find the cause: Ferritin, iron/ total iron-binding capacity (p. 231); hepatitis serologies; quantitative immunoglobulins (p . 232); autoantibodies (ANA, AMA, SMA); AFP (p. 219) level; ceruloplasmin (p. 233); Live r ultrasound may show hepatomegaly, splenomegaly, focal liver lesion(s), hepatic vein throm bi, reversal of flow in the portal vein, or ascites. MRI: Caudate lobe size ^ , smaller isl ands of regenerating nodules, and the pres- ence of the right posterior hepatic notch are m ore frequent in alcoholic cirrhosis than in virus-induced cirrhosis. MRI scoring systems ba sed on spleen volume, liver volume, and the presence of ascites or varices/collater- als ca n quantify the severity of cirrhosis in a manner that correlates well with Child \200\223Pu gh grades (see Table 7.12). Ascitic tap should always be performed if ascites is present an d fluid should be sent for urgent cell count, C&S: An ascitic neutrophil count of >250/mm 3 indicates spontaneous bacterial peritonitis. Also, a total WBC >500/mm 3 indicates SBP. Li ver biopsy confirms the clinical diagnosis. This may be done ultrasound-guided and percutan eously (if the INR \211 1.5 and the platelet 227 1 -antitrypsin (p. 233). count \211 50 K) or via the transjugular route with FFP or activated recombi- nant Factor VII. Management General: Maintain good nutrition; low-sodium diet (espe- cially if ascites ); alcohol abstinence; avoid NSAIDs, sedatives, and opiates; vaccinate against HAV and HBV; cholestyramine may help pruritus (4 g PO bid, 1 h after other drugs). Perform ultrasound e very 6 months to screen for hepatocellular cancer (HCC). Consider adding AFP; however, rece nt data indicate that AFP levels lack sensitivity and specificity for diagnosis or surveill ance (p. 236). Specific treatments : For hcv-related cirrhosis , treatment with pegylated i nterferon- plus ribavirin and new protease inhibitors improves liver bio- chemistries an d may prevent the development decompensated liver disease and/or HCC. Meta-analyzes show so me benefit of low-dose ursodeoxycholic acid (URSO) in PBC. There is increased mortality in primary sclerosing cho- langitis (PSC) with use of high-dose URSO, and the AASLD recommends against initiation of URSO in PSC. Penicillamine or Trientine for Wilson \200\231s disease (p. 233), aggressive phlebotomy for hereditary hemochromatosis. Ascites: Fluid restriction (<1.5 L/d), low-sodium diet (40 \200\223100 mmol/d). Spironolactone (Aldactone), start 50 \200\223100 mg/24 h PO (usually given in two divided doses as bid); increase dose q48h to 4 00 mg/24 h if necessary to control ascites and edema; carefully monitor serum K + levels; c hart daily weights, aim for weight loss of 0.5 kg/d. If response to Aldactone is poor, add furosemide 40 \200\223120 mg/24 h PO (usually given in a ratio of 4:10 with Aldactone \200 \224e.g., furosemide 40 mg and Aldactone 100 mg, or furosemide 80 mg and Aldactone 200 mg); check BUN/creatinine and serum Na + often. Therapeutic paracentesis with concomitant album in infusion (6 \200\2238 g/L fluid removed) may be tried; albumin infusion during large vol ume paracentesis may prevent HRS. Spontaneous bacterial peritonitis: Treatment : E.g., ceft riaxone 1 \200\2232 g/24 h or Zosyn 3.375 g q6 h (pay special attention to dosing; it depen ds on degree of liver failure and renal failure); fine-tune antibiotic coverage after the s ensitiv- ities are known. Prophylaxis: Bactrim DS tab PO 3 \200\2235 \227 a week; norfloxa cin 400 mg PO qd; ciprofloxacin 750 mg PO every week. Prognosis Overall, 5-yr survival is 50%. Poor prognostic indicators: Encephalopathy, serum Na + <110 mEq/L, serum albumin <2.5 g/dL, \206\221 INR. Liver transplantation is the only definitive treatment for cirrhosis. This increases 5-yr survival from 20% in end-stage disease to 70%. Model for End-Stage Li ver Disease (MELD) Score : (1 \200\22340). Predicts 90-day mortality for cirrhotic patients under consideration for transplant. Calculated via complex formula calculator from basic c omponents: INR, total bilirubin, creatinine (Cr). 228 Table 7.11 Causes of cirrhosis \212 \212 \212 Chronic alcohol abuse Chronic HBV or HCV infection Autoimmune disease: PBC (p. 220), PSC (p . 221), autoimmune hepatitis Genetic disorders: (p. 218), hereditary hemochromatosis (p. 21 6) Others: Budd \200\223Chiari syndrome (hepatic vein thrombosis) Drugs: E.g., amiodarone, methyldopa, methotrexate \212 1-Antitrypsin deficiency (p. 219), Wilson \200\231s disease \212 \212 y g o o r e t n e o r t s a G Table 7.12 Child \200\223Pugh grading and risk of variceal bleeding Risk ^^ if score \211 8 l 1 point <2 >3.5 <1.7 None None 2 points 2 \200\2233 2.8 \200\2233.5 1.7 \200\2232.3 Slight 1 \200\2232 3 points >3 <2.8 >2.3 Moderate 3 \200\2234 Bilirubin (mg/dL) Albumin (g/dL) INR Ascites Encephalopathy Alcoholism An alcoholic is one whose repeated drinking leads to harm in his or her work or social life. Denial is a leading feature of alcoholism, so it may be helpful to query relat ives. Screening tests: Mean cell volume (MCV) ^ ; GGT ^ . See Table 7.13. CAGE questions Sc reening for alcohol abuse Have you ever : Felt you ought to CUT DOWN on your drinking? Had people ANNOY you by criticizing your drinking? Felt bad or GUILTY about your drinking? Had a drink in the AM (eye-opener) to steady your nerves? CAGE is quite good at detecting alcoh ol abuse and dependence (1 point for each +, more than 2 points is significant; sensitivity , 43 \200\22394%; specificity, 70 \200\22397%). Organs affected by alcohol The liver: (Norm al in 50% of alcoholics) Fatty liver: Acute and reversible, but may progress to cirrhosis i f drink- ing continues (also seen in obesity, DM, and with certain medications). Cirrhosis : 5-yr survival is 48% if drinking continues (if not, 77%). Hepatitis: TPR ^ , anorexia, te nder hepatomegaly jaundice, bleeding, ascites, WBC ^ , INR , AST ^ , MCV ^ , urea ^ ( HRS). 80% progress to cirrhosis (hepatic fail- ure in 10%). Biopsy: Mallory bodies neutr ophil infiltrate. Treatment: See Table 7.14. \212CNS: Poor memory/cognition: Multiple high -potency vitamins IM may reverse it; cortical atrophy; retrobulbar neuropathy; fits; falls; wide-based gait neuropathy; Korsakoff Wernicke encephalopathy 229 \212 Gut: Obesity, diarrhea; gastric erosions; peptic ulcers; varices; pancreatitis (acute and chronic) \212Blood: MCV ^ ; anemia from marrow depression, GI bleeds, alcoholism-associated folate deficiency, hemolysis; sideroblastic anemia \212Heart: Arrhyt hmia; BP ^ cardiomyopathy; sudden death in binge drinkers Withdrawal signs Pulse ^ , BP , tremor, fits, hallucinations ( delirium tre- mens ) may be visual or tactile (e.g., of an imals crawling under one \200\231s skin). Alcohol contraindications Driving, hepatitis, cir rhosis, peptic ulcer, drugs (e.g., antihistamines), carcinoid, pregnancy (fetal alcohol syn drome: IQ , short palpebral fissure, absent filtrum, and small eyes). Management Alcohol withdrawal: Admit; do BP + TPR/4 h. Beware BP . For the first three days give generous chlordiazepoxide (e.g., 10 \200\22350 mg/6 h PO), weaning over 7 \200\22314 d. Watch for pe rsistent withdrawal and add benzo- diazepine to keep BP stable; if deteriorating consider I CU management with intubation, benzodiazepine or propofol sedation in severe cases as neede d. Vitamins required (thiamine, folate, etc.). Treating established alcoholics may be rewarding, particularly if they really want to chang e. If so, group therapy or self-help (e.g., Alcoholics Anonymous) may be useful. Relapse: 5 0% will relapse in the months following initiation of treatment: Anxiety, insomnia, and cra ving may be intense, and is mitigated by acam- prosate. CI: Pregnancy, severe liver failure , creatinine >120 mmol/L. SE: Diarrhea and vomiting (D&V), libido ^ or . Dose example: 6 66 mg/8 h PO if >60 kg and <65yrs old. Reducing pleasure that alcohol brings (and decreasin g craving): Naltrexone 50 mg/24 h PO can halve relapse rates. SE: Vomiting, drowsiness, diz ziness, cramps, arthralgia. CI: Liver failure. It is costly. Confer with experts if drugs a re to be used. Table 7.13 Patterns of lab tests in alcoholic and other liver disease AST Aspartate aminotransferase ^^ (twice as high as alt) ^ or * ALT Alanine aminotransferase ^ MCV Mean cell volume Alcoholic liver disease ^^ Hepatitis C (HCV) Nonalcoholic fatty liver disease ^^ (higher than ast) ^^ ^ ^ or 230 In HCV, AST:ALT ratio is typically <1; ratio may reverse if cirrhosis develops. GGT may be ^^ in alcoholic liver disease, but is rather nonspecific. Table 7.14 Managing alcoholic hepatitis Stop alcohol consumption (for withdrawal symptoms, if chlordiazep- oxide by the oral route is impossible, try lorazepam IM). High-dose B vitamins IV Optimize nutrition (35 \200\22340 kcal/kg/d nonprotein energy) + 1.5 g/kg/d of protein (use ideal body weight for calculatio ns; e.g., if malnourished). This prevents encephalopathy, sepsis, and some deaths. Daily we ight; LFT; basic metabolic panel (BMP); INR. If creatinine \206\221 , get help with this h epatorenal syndrome (i.e., renal failure where the underlying pathology is hepatic). Na + \206\223 is common, but water restric- tion may make matters worse. Culture ascites fluid; give appropriate antibiotics in the light of sensitivities. If no active infection or GI bl eeding consider adjunct medical therapy with Maddrey score >32: Prednisolone 40 mg/d for 5 d tapered off over 3 wks MAY help. Pentoxifylline may be helpful for acute alcoholic hepati tis. Liver transplantation is not an option for patients with acute alcoholic hepatitis or without history of documented abstinence, but some centers may consider them after 6 months of rehab/abstinence. Maddrey Score = 4.6 (patient \200\231s PT \200\223 control PT) + tot al bilirubin (mg/dL) (poor prognosis if score \211 32). \212 \212 \212 \212 \212 \212 Hereditary hemochromatosis Hereditary hemochromatosis (HH) is an inherited disorder of iron metabo- lism in which increased intestinal iron absorption leads to its deposition in mult iple organs (joints, liver, heart, pancreas, and pituitary). Middle-aged males are more fre quently and severely affected than women, in whom the disease tends to present 10 yrs late r (menstrual blood loss is protective). Disease onset is usually at 40 \200\22350 yrs in me n and 50 \200\22360 yrs in women. Genetics HH is one of the most common inherited diseases in those of Northern European ancestry (carrier rate of 1 in 10 and a frequency of homozyg osity of 1:200 \200\2231:400). The gene responsible for most HH is the HFE gene located on chromosome 6. Two major mutations are termed C282Y and H63D. C282Y accounts for 60 \200 \223100% of HH, and H63D accounts for 3 \200\2237%, with compound heterozygotes accounting for 1 \200\2234%. Penetrance is unknown but is clearly <100%. Clinical features Asymptomati c early on, then fatigue, weakness, leth- argy and arthralgias (MCP and large joints) usual ly develop. Later, look for slate-gray skin pigmentation, DM ( \200\234bronze diabetes \200 \235), and stigmata of chronic liver disease. Hepatomegaly early on; small and shrunken cir - rhotic liver later; heart failure (dilated cardiomyopathy) and conduction disturbances; h ypogonadism (pituitary dysfunction, or via cirrhosis) and associated osteoporosis. Other en docrinopathies include hyporeninemic hypoaldosteronism. Tests Blood: Abnormal LFT, \206 \221 serum ferritin; \206\221 serum iron-to-TIBC ratio; transferrin saturation >60%, often >80%. HFE genotyping. Blood glucose to look for DM. Joint x-rays may show chondrocalcinosi s. Liver biopsy: Perl stain quantifies iron loading (hepatic iron index [HII] >1.9 mcmol/kg /yr) and assesses disease severity. MRI also helps estimate hepatic iron loading. Do ekg an d echo if you suspect cardiomyopathy. Management Phlebotomize 1 U/wk until mildly iron-def icient. Iron will continue to accumulate, so maintenance phlebotomy (1 U q2 \200\2233 month s) is needed for life. Maintain hemoglobin at about 10 \200\22312 g/dL, serum ferritin 50 \200\223100 ng/mL, and transferrin saturation <50%. Other monitoring: Diabetes; Hb A1c leve ls may be falsely low as phlebotomy reduces the time available for Hb glycosylation. Over-t he-counter self-medication: Make sure that vitamin preparations etc. contain no iron. Scree ning: Test serum ferritin, transfer- ring saturation, and genotype in first-degree relative s. Prevalence of iron overload in asymptomatic C282Y homozygotes is 4.5 per 1,000 persons s creened. Fewer than 10% of C282Y homo will develop severe iron over- load and organ damage. Prognosis Phlebotomy returns life expectancy to normal if noncirrhotic and nondiabetic. Ar thropathy may not improve or even worsen. Gonadal failure is irreversible. In noncirrhotic patients, phlebotomy may improve liver histology. Cirrhotic patients have >10% chance of de veloping HCC. Sources vary on the exact risk: Some authorities quote 30%, others 22%. One c ause of variability is varying cofactors: Age >50 yrs increases risk by 13-fold; being HBsA g positive by fivefold, and alcohol abuse by twofold. Secondary hemochromatosis may occur i n any hematological condi- tion where many transfusions ( 80 U) have been given. To reduce the need for transfusions, find out if the hematological condition responds to eryth- ropoi etin or marrow transplantation before the irreversible effects of iron overload become too great. y g o o r e t n e o r t s a G l 231 Autoimmune hepatitis AIH is an inflammatory liver disease of unknown cause characterized by suppressor T-cell defects with autoantibodies directed against hepatocyte surface antigens . This disease is a steroid-responsive hepatitis. Two types are distinguished by the presen ce of circulating autoantibodies: Affects both adults or children Antinuclear antibodies (ANA) and/or Anti-smooth muscle anti bodies (ASMA) positive in 80%. Other autoantibodies associated with type I include: Anti-so luble liver Ab (ASLA), anti-dsDNA Ab, and p-ANCA. Type I Type II Affects children; generally girls and some young women Anti-liver/kidney microsomal type 1 (ALKM-1) antibod- ies. Other autoantibodies associated with type II include: Antiliver cyto sol antigen (ALC-1) Clinical features Predominantly affects young and middle-aged women. 25% of patients presen t with acute hepatitis and features of an autoimmune disease (e.g., fever, malaise, urticar ial rash, polyarthritis, pleurisy, or glom- erulonephritis). The remainder present insidiou sly or are asymptomatic and diagnosed incidentally with signs of chronic liver disease. Ame norrhea is Associations Pernicious anemia \220 Autoimmune hemolysis Ulcerative colitis (UC) Diabetes Glomerulonephritis Human leukocyte antigen (HLA) A1, B8, & DR3 haplotype 232 Autoimmune thyroiditis \220 PSC PBC common. Tests Abnormal LFT (AST/ALT \206\221 ), hypergammaglobulinemia (especially IgG), p ositive autoantibodies: ANA, ASMA, ALKM-1, etc. (see above). Anemia, leukopenia, and thromb ocytopenia indicate hypersplenism. Liver biopsy shows a mononuclear infiltrate (usually pla sma cells) within the portal, then periportal areas. This may be followed by piecemeal necr osis, bridging fibrosis, or cirrhosis. ERCP helps exclude PSC if the alk phos is disproport ionately elevated. Diagnosis depends on excluding other diseases as there is no pathog- nom onic sign or lab test. There is genuine overlap with PBC. Diagnostic criteria exist but are not fully validated. Management Prednisone 30 \200\22340 mg/d PO for 1 month; decrease by 5 mg a month to a maintenance dose of 5 \200\22310 mg/d PO. Corticosteroids can sometimes b e stopped after a few years, but relapse occurs in 50 \200\22386%. Azathioprine (50 \200 \223100 mg/d PO) may be used alone as a steroid-sparing agent or in combination with lower doses of prednisone. Remission is achievable in 80% of patients within 3 yrs. 10- and 20-yr survival rates: >80%. The goal is to achieve a sustained remission without the need for fu rther drug therapy; achievable in 10 \200\22340% of patients overall. Second-line therapies : Mycophenolate mofetil, budesonide, cyclosporin, tacrolimus, ursodeoxycholic acid, methot rexate, cyclophosphamide, 6-mercaptopurine, and free radical scavengers. Liver transplantation is indicated for decompensated cirrhosis, but recurrence may occur. P ost-transplant 10-yr survival rate is 75%. y g o o r e t n e o r t s a G l Wilson \200\231s disease/hepatolenticular degeneration A rare inherited disorder with toxic accumulation of copper (Cu) in liver and CNS (especially basal ganglia; e.g., globus palli dus hypodensity puta- men cavitation). It is treatable, so screen all young patients wit h evidence of liver disease. Genetics: Autosomal recessive (gene on chromosome 13; codes fo r a copper transporting ATPase, ATP7B). Twenty-seven mutations are known; HIS1069GLU is the most common. Signs Children usually present with liver disease (hepatitis, cirrhosis, ful- minant hepatic failure); young adults often start with CNS signs: Tremor, dysarthria, dysp hagia, dyskinesias, dystonias, purposeless stereotyped movements (e.g., hand clapping), dem entia, parkinsonism, micrographia, ataxia/clumsiness. Affective features : Depression/mania , labile emotions, \206\221 libido, personality changes. Cognitive/behavioral: Memory defi cits, quick to anger, slow to solve problems, decline in IQ. Psychosis: Delusions, mutism. Kayser \200\223Fleischer rings: Cu deposits in the cornea around the iris (Descemet membran e), pathognomonic but not always present; may need slit lamp to detect. Also: Hemolysis, bl ue lunulae (nails), polyarthritis, hypermobile joints, gray skin, hypoparathyroidism. Tests Serum copper and ceruloplasmin usually low. 24 h urinary cop- per excretion is elevated (> 100 mcg/24 h, normal <40 mcg). Liver biopsy: Elevated hepatic copper content. Molecular gen etic testing can confirm the diagnosis. MRI: Basal ganglia degeneration ( frontotemporal, cerebellar, and brainstem atrophy). Management Diet : Low-copper diet (avoid shellfish, nu ts, chocolate, mush- rooms, organ meat). Chelation: Lifelong penicillamine (1,000 \200\2231 ,500 mg/24 h in 2 \200\2234 divided doses for the first 4 \200\2236 months; then maintenanc e dosing at 750 \200\2231,000 mg/24 h in 2 divided doses). se: Nausea, rash, leukopenia, an emia, thrombocytopenia, hematuria, nephrotic range proteinuria, lupus. Watch closely for th ose patients with a known penicillin (PCN) allergy \200\224they will likely have a reaction to penicillamine as well. Monitor CBC and urinary Cu (and protein) excretion. Stop if WBC is <2.5 \227 10 9 /L or platelets falling to <100 k. Alternative : Trientine dihydrochlori de 750 \200\2231,500 mg/24 h in 2 \200\2233 divided doses ( se: Rash; sideroblastic anemia) . Adjunct : Zinc. Liver transplant if severe liver disease. Screen siblings as asymptomatic homozygotes need treatment. ALF If presentation with acute liver failure, refer to transpl ant center immediately. Development of refractory coagulopathy, hemolytic anemia, and renal insufficiency due to copper build up may only respond to plasma exchange transfusion or tr ansplant. Transplant is curative. Prognosis Precirrhotic liver disease is reversible. Neuro logical damage less so. Death occurs from liver failure, variceal hemorrhage, or infection (the typical complications associated with end-stage liver disease). 233 1 -Antitrypsin deficiency 1 -Antitrypsin is one of a family of serine protease inhibi tors controlling inflammatory cascades. It is synthesized in the liver, making up 90% of se rum -globulin on electrophoresis. 1 -antitrypsin deficiency is the chief genetic caus e of liver disease in children. In adults, its deficiency causes emphysema, chronic liver d isease, and HCC. Other associations: Asthma, pancreatitis, gallstones. Decreased risk of st roke. Prevalence: 1:2,000 \200\2231:7,000. Genetics Carrier frequency: 1:10. Genetic variants are typed by their elec- trophoretic mob ility as medium (M), slow (S), or very slow (Z). S and Z types are due to single amino acid substitutions at positions 264 and 342, respectively. These result in diminished productio n of 1 -antitrypsin (S = 60%, Z = 15%). The normal genotype is PIMM, the homozygote is P IZZ; heterozygotes are PIMZ and PISZ. Symptomatic patients (e.g., cholestatic jaundice /cir rhosis; dyspnea from emphy- sema) usually have PIZZ genotype. nb: Cholestasis often remits in adoles- cence. In adults, cirrhosis HCC affects 25% of all 1 -antitrypsin-deficien t individuals >50 yrs. Tests Serum 1 -antitrypsin levels are low. Liver biopsy: Periodic acid Schiff (PAS) positive; diastase-resistant globules. Phenotyping by isoelectric focus- ing requires expertise to distinguish SZ and ZZ phenotypes. Prenatal diag- nosis is possib le by DNA analysis of chorionic villus samples obtained at 11 \200\22313 wks gestation. DNA tests are likely to find greater use in the future. Management Supportive for emphysema an d hepatic complications. Smoking cessation; consider augmentation therapy with human 1 - antitrypsin if FEV1 <80% of predicted (expensive!) liver transplant in decompensated cir rhosis. Primary biliary cirrhosis In PBC, the interlobular, intrahepatic bile ducts are damaged by chronic granulomatous inflammation causing progressive cholestasis, cirrhosis, and portal h ypertension. Cause: Possibly autoimmune. F:M ratio approaches 9:1. Prevalence: 19 \200\2235 1 cases per million population. Peak presentation: 50 yrs. Clinical features 50 \200\22360 % of patients are asymptomatic and diagnosed only after finding \206\221 alk phos on routi ne LFTs. Lethargy and pruritus are the most common symptoms in symptomatic patients, and th ey may precede jaundice by months to years. Signs : Jaundice, skin pigmentation (due to mel - anosis), xanthelasma, xanthomata, hepatomegaly, and splenomegaly. Complications: Osteopor osis is common. Malabsorption of fat-soluble vita- mins (A, D, K, E) is uncommon but in cir rhotic patients may result in osteomalacia and coagulopathy. Other complications: Portal hy pertension, ascites, variceal hemorrhage, hepatic encephalopathy, HCC (p. 305). Tests Blood tests: \206\221 Alk phos, \206\221 GGT and 5 \200\231-nucleotidase levels, and mildly \206\221 AST and ALT; late disease: \206\221 Bilirubin, low albumin, \206\221 PT/INR. 98% are AMA M 2 subtype positive (highly specific). Other autoantibodies, such as ANA, may occ ur in low titers. Immunoglobulins are elevated (especially IgM). TSH and cholesterol may be elevated. Radiology: Ultrasound, and ERCP or MRCP to exclude extrahepatic cholestasis. Liv er biopsy: Granulomas around the intrahepatic bile ducts, progressing to cirrhosis. Classic ally, nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. Tr eatment Symptomatic: Pruritus: Try cholestyramine 4 g PO bid \200\223tid. Diarrhea (usually from steatorrhea): PRN Imodium or loperamide; can also use pancreatic enzymes as there is often an associated pancreatic insuf- ficiency as well. Osteoporosis prevention (p. 305). 5 Specific: Fat-soluble vitamin prophylaxis: Vitamins A, D, and K. Consider ursodeoxycholic acid (UDCA), 13 \200\22315 mg/kg/d to all patients, which may obvi- ate the need for liver transplantation , which is the last recourse for patients with end-stage disease and/or int ractable pruritus. Recurrence in the graft 234 5 . Lindor et al. AASLD Practice Guidelines: Primary biliary cirrhosis. Hepatology . 2009;5 0(1 ):291 \200\223308. may occur but appears not to influence graft success. Other therapies that have been tried besides UCDA include colchicine and methotrexate. Prognosis Once jaundice develops, surviva l is <2yrs. In one study, at 2 yrs post-transplant, predicted survival without retransplant was 55% and actual survival was 79%. At 7 yrs, these figures were 22% and 68%, respectivel y. y g o o r e t n e o r t s a G l