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Home , Alcoholic hepatitis, Alcoholic liver disease, Chronic liver disease

CME General Internal Medicine for the Physician – II

Acute function and the results of other weight gain, but in severe forms oedema standard liver tests are otherwise normal and may be present. Bruising may in all three conditions. be spontaneous or at sites of venepunc- ture. Serum biochemistry shows increase Andrew Burroughs FRCP in transaminases, while serum albumin Lucy Dagher MD levels may be low and prothrombin time & Hepatobiliary Generalised impairment of hepato- prolonged. Medicine, Royal Free Hospital, London cellular function may result from acute liver injury or chronic disease. A variety Obstruction of the bile ducts Clin Med JRCPL 2001;1:285–9 of disorders can produce acute or subacute hepatocellu lar injur y The bile ducts may be obstructe d including: because of mechanical obstruction of the The normal serum concentra- • viral biliary tree by the presence of stones or tion in adults is less than 18 mmol/l. exposure to hepatotoxins by intrinsic disorders of the and Jaundice is best looked for in the sclerae • extrinsic compression, most commonly hepatic ischaemia and mucous membrane of the soft palate • and carcinoma of and is a common sign in almost all liver • certain metabolic derangements. the pancreas, respectivel y. Without and diseases. There are sev- Jaundice appears over days or weeks. mechanical obstruction the most eral important questions of value in and malaise are common. There common causes of cholestatic jaundice determining the diagnosis which the may be varying degrees of decompensa- are drug induced and following hepatitis clinician should ask himself/herself: tion due to or just cutaneous A. The patient does not have signs of 1Is the jaundice due to an markers of . Signs of chronic liver disease but may have signs obstruction of the biliary tree? , if present, may indicating malignancy. Pruritus is usual, 2Is there evidence of chronic liver be personality change, and in more and the patient becomes increasingly disease? severe cases manifest as flapping tremor, pigmented. There are raised levels of confusion and coma. Fluid retention in conjugated bilirubin , biliar y alkaline 3Is the jaundice possibly drug its mildest form may be exhibited as phosphatase and total cholesterol in the induced, induced or infective in origin? 4Is there any evidence of haemolysis? Fig 1. Classification of jaundice.

Classification of jaundice (Fig 1) JAUNDICE Jaundice can result from either an increase in bilirubin formation or a decrease in hepatic clearance. From a Hepatocellular practical standpoint, it is reasonable to Isolated bilirubin Cholestatic classify conditions that produce jaundice transport defects haemolysis under three broader categories: Acute Chronic 1Isolated disorders of bilirubin Dilated ducts Undilated ducts metabolism. 2Liver disease. 3Obstruction of the bile ducts. Table 1. Disorders of bilirubin metabolism.

Unconjugated hyperbilirubinaemia: Isolated disorders of bilirubin Increased bilirubin production Haemolysis metabolism (Table 1) Ineffective erythropoiesis The mechanisms that can lead toisolated Blood transfusion Resorption of haematomas unconjugated hyperbilirubinaemia are: Decreased hepatocellular uptake Drugs (eg rifampicin) • increased bilirubin production Gilbert syndrome • decreased hepatocellular uptake Decreased conjugation Gilbert syndrome decreased bilirubin conjugation. Crigler-Najar syndrome • Physiologic jaundice of the newborn Hyperbilirubinaemia is often associ- Conjugated or mixed hyperbilirubinaemiaD ubin-Johnson syndrome ated with a predominant elevation in Rotor syndrome indirect serum bilirubin concentration.

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Key Points some can cause haemolysis. Drug inges- tion may need to be sought by searching Scleral jaundice can be detected if serum bilirubin is above 34 mmol/l, but more the patient’s home and workplace and by commonly 50 mmol/l is the threshold re-taking the history as well as checking general practitio ner (GP) records. A careful history, physical examination and review of the standard laboratory tests Ingestion of significant quantities of should allow a physician to make an accurate diagnosis in 85% of cases paracetamol or the mushroom Amanita In acute jaundice, liver ultrasound should be the first imaging modality phalloides may lead to hepatocellular and jaundice within several days If there is evidence of biliary obstruction and a therapeutic intervention is planned, of exposure 2. Toxic liver injury can have a endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography is the investigation of choice fulminant course associated with a high mortality. Several drugs can produce Magnetic resonance cholangiopancreatography should follow ultrasound if the idiosyncratic hepatocellular injury and latter has been technically difficult, if obstruction has not been ruled out or jaundice, the most common being non- therapeutic intervention is not needed steroidal anti-infla mmatory drugs is needed to confirm the presence, cause and severity of chronic liver (NSAIDs), , terbinafine, iso- disease niazid, methyldopa, phenytoin and the inhalational anaesthetic halothane. Excessive alcohol intake is especially serum. Steatorrhoea is responsible for increased exposure not only to viral important because it is common; a weight loss and of cal- hepatitis but also to a greater number of detailed history of alcohol consumption cium and fat-soluble vitamins A, D, E rarer causes of jaundice such as , should be taken from the patient, rela- and K. and inherited haemoglobinopathies. A tives and the GP . In adult patients with new onset of family history is important with regard should be a diagnostic consideration in jaundice, eight disorders account for to heritable disorders of bilirubin metab- the jaundiced patient with 98% of the diagnoses ultimately olism such as Gilbert syndrome, chronic dependency, particularly when hepato- established 1: liver disease such as Wilson’s disease, megaly and fever are present. haemochromatosis and autoimmune • Physical examination conditions which may be associated with • chronic active hepatitis or PBC. Special chronic hepatitis • attention should be paid to identifying • drug induced liver diseases groups at particular risk of contracting A history of fever, especially accom- • and their complications infective viral hepatitis such as intra- panied by shaking chills, or abdominal • carcinoma of the pancreas venous (IV) drug abusers, homosexuals, pain particular ly in the right upper • primary biliary cirrhosis (PBC) following needle-stick injuries or contact quadrant, is suggestive of cholangitis primary sclerosing cholangitis. with jaundiced individuals, and patients caused by obstructive diseases (particu- • who have received blood transfusions. larly choledocholithiasis), as is a history By the time patients with metastatic Drugs and environmental hepato- of biliary surgery. Symptoms compatible liver disease develop jaundice, the diag- may not only be hepatotoxic but with viral prodrome, such as anorexia, nosis is usually obvious because the liver has been extensively replaced by tumour tissue. Fig 2. History taking in acute jaundice. Careful history, physical examination Raw fish and review of standard laboratory tests Transfusion and Newborns of should allow a physician to make an transplant recipients long-term carriers accurate diagnosis in 85% of cases 1. Alcohol Multiple Family history sexual partners History History (Fig 2) Intravenous Prescription taking drug users An accurate clinical history is medication in acute Over-the-counter jaundice particularly important in differentiating drugs Prisoners the various causes of jaundice. In con- Vitamins Institutionalised junction with examination, it determines Herbal remedies people the most appropriate investigations. Healthcare Body-piercing, The increase in foreign travel and workers Hepatoxins tattoos migration to developed countries have

286 Clinical Medicine Vol 1No 4 July/August 2001 CME General Internal Medicine for the Physician – II

Table 2. Signs and symptoms of viral hepatitis. aspartate aminotransfer ase to alanine aminotransferase appears to be a useful Infection index for distinguishing non-alcoholic Short-term Long-term (NASH) from alcoholic (acute) (chronic) liver disease. Although ratios less than 1 suggest NASH or viral hepatitis, a ratio Tiredness, anorexia, malaise, myalgias Same symptoms as acute of 2 or above strongly suggests alcoholic or stomach ache Muscle and joint ache liver disease 3,4. Gamma-glutamyl trans- Diarrhoea Weakness Skin rash Signs & symptoms of cirrhosis ferase elevation strengthens the diagnosis Yellow eyes/skin (jaundice) Signs & symptoms of of . A drug effect is possible Light-coloured stools Secondary amenorrhoea if there is a correlation between the onset Dark yellow urine of jaundice, elevation of liver and the start of drug administration. The drugs that most commonly cause malaise and myalgias point to viral which the liver is usually enlarged. The transaminase abnormalities are NSAIDs, hepatitis (T able 2). Systemic features of edge is tender in hepatitis, congestive HMG-CoA reductase inhibitors, anti- malignancy should be sought (eg weight , bacterial cholangitis, occa- epileptic drugs and antituberculosis loss, anaemia, anorexia), especially if of sionally in malignant liver disease, and drugs. In addition to prescribed medica- short duration. These symptoms in with alcoholic hepatitis or severe fatty tion, over-the-cou nter medication s, conjunction with painless jaundice, liver. An arterial murmurover the liver herbal preparations and illicit drug use particularly in a middle-aged or older indicates acute alcoholic hepatitis, liver may also be the cause. The first step to person, suggest neoplasm of the head of cancer or an arteriovenous fistula. determine whether a medication or the pancreas. alcohol is responsible is to stop the Scleral jaundice can be detected if Investigations (Fig 3) potential injurious agent and see serum bilirubin is above 34 mmol/l, but whether the tests return to normal. more commonly 50 mmol/l is the The pattern of the liver tests may If the abnormalities persist, particu- threshold. Needle marks should suggest be helpful, with additional testing to larly if transaminase values remain high, IV drug abuse. Skin excoriations confirm identify a cause of jaundice. The ratio of markers of autoimmune disease should that the patient has been scratching; this may be particularly severe in patients Fig 3. An algorithm for investigation in the patient with acute jaundice (AMA = with PBC and primary sclerosing antimitochondrial antibody; CT = computed tomography; ERCP = endoscopic retrograde cholangitis. Three physical findings indi- cholangiopancreatography; MRCP = magnetic resonance cholangiopancreatography; cate that a patient is almost certainly MRI = magnetic resonance imaging). drinking excessive amounts of alcohol:

parotid enlargement Evaluate for haemolysis, • normal gynaecomastia transaminases hereditary • hyperbilirubinaemia • Dupuytren’s contracture. Evidence of (ie elevated ascites, splenomega ly, prominent abdominal veins) and/ or spider angiomata, gynaecomastia and suggest the presence of chronic paren- Hepatobiliary chymal liver disease. Certain physical Ultrasound findings may suggest particular liver diseases, for example pigmentation in normal AMA, consider viral hepatitis, alpha-fetoprotein, ERCP chronic biliar y disease and haemo- chromatosis, xanthomas in PBC, and bile duct Cholangiography (MRCP, Kaiser-Fleischer rings in Wilson’s disease. dilatation ERCP as indicated) Dilated peri-umbilical veins indicate a portal collateral circulation in cirrhosis, focal lesions CT/MRI Arteriography, biopsy while ascites may be due to cirrhosis or malignant disease. A very large nodular liver suggests cancer. A small liver may Above negative and LIVER BIOPSY indicate severe hepatitis or cirrhosis, elevation persists excluding intrahepat ic in

Clinical Medicine Vol 1No 4 July/August 2001 287 CME General Internal Medicine for the Physician – II be sought, especially in young women. patients who have undergone previous is cost: ERCP is more expensive than Serologic studies for and cholecystectomy. non-invasive procedures. C should be done in all patients, and iron studies routinely obtained to assess Computed tomography of the Percutaneous transhepatic the possibilit y of haemochromatosis. abdomen cholangiography Caeruloplasmin and copper levels are appropriate routine tests in patients up Abdominal computed tomography (CT) Percutaneous transhepati c cholangio- to the age of 45 years to detect Wilson’s permits accurate measurements of the graphy (PTC) complements ERCP . Its disease. Alpha 1-antitrypsin levels should calibre of the biliary tree, w ith a sensitivity (98– 100%) and specificity be evaluated if the above measurements sensitivity of 63–96% and a specificity of (89–100%) for the diagnosis of biliary fail to explain the aetiology of persis- 93–100% for detecting biliary obstruc- tract obstruction are comparable with 2 tently raised aminotransferases. tion . Spiral (helical) CT improves the those of ERCP 7. Like ERCP, it is recom- All patients with persistent jaundice of diagnostic accuracy of this method. mended when interventional procedures uncertain cause should be advised to Abdominal CT also detects space- are needed, such as balloon dilatation discontinue unnecessar y medicatio ns occupying lesions as small as 5 mm. and stent placement to relieve amenable and abstain from alcohol for several Unlike ultrasonog raphy, CT is not focal obstructions of the biliary tree. PTC weeks and then be tested again. If the operator dependent and it provides is preferred when the level of biliary alkaline phosphatase is elevated, technically superior images in obese obstruction is proximal to the common ultrasound scanning should be per- patients in whom the biliary tree is hepatic duct or where altered anatomy formed to exclude biliary obstruction obscured by bowel gas. CT is not as precludes ERCP. PTC may be technically and space-occupying lesions. A normal accurate as ultrasonography in detecting limited in the absence of dilatation of the ultrasound suggests chronic cholestatic cholelithiasis because only calcified intrahepatic bile ducts. Morbidity (3%) or infiltrative disease. stones can be seen clearly. Other consid- and mortality (0.2%) of PTC are due to erations in the use of abdominal CT in bleeding, perforation and cholangitis. patients with jaundice are its lack of Radiology portability, requirement of IV contrast Magnetic resonance imaging Liver ultrasound and expense. Magnetic resonance imaging is an The sensitivity of ultrasound to dilata- Endoscopic retrograde increasingly useful investigation of tion of the bile ducts has made it the cholangiopancreatography hepatobiliary disease, especially in diag- imaging technique of choice in the nosing and staging malignant disease. evaluation of jaundice 5. If clinical history Direct visualisation of the biliary tree as Alterations in weighting of the image and laboratory tests suggest obstructive well as the pancreatic ducts is possible lead to prominence of the ductal system aetiology in acute jaundice, liver ultra- with endoscopic retrograde cholangio- in the biliary tree and pancreas, known sound should be the first imaging pancreatography (ERCP). ERCP is more as magnetic resonance cholangio modality and it is considered the ‘stetho- invasive than abdominal ultra- pancreatography (MRCP). The basic scope’ of the hepatologist. It can confirm sonography and CT and requires principle of MRCP is to utilise T2- or exclude obstruction, signs of chronic conscious sedation. It is highly accurate weighted images in which stationary or liver disease and space-occupying in the diagnosis of biliary obstruction, slowly moving fluid, including bile, is lesions. The sensitivity of abdominal with a sensitivity of 89–98% and a high in signal intensity and all ultrasonography for the detection of specificity of 89–100% 6. In addition to surrounding tissues, including retroperi- biliary obstruction in jaundiced patients providing radiographic images, biopsy toneal fat and solid visceral organs, are ranges from 55–91% and the specificity specimens and brushings for cytology lower in signal. MRCP is a promising from 82–95% 2. Ultrasonog raphy can or periampullary lesions can be obtained new tool that provides detail of the liver also demonstrate cholelithia sis and at ERCP. Moreover, if a focal cause of bil- parenchyma and biliary tree 8. MRCP can space-occupying lesions greater than iary obstruction is identified (eg chole- be employed: 1 cm in diameter. The major advantages docholithiasis, stricture), manoeuvres to • when there are contraindications to of ultrasound are that it is non-invasive, relieve the obstruction (eg sphincterec- or failure of ERCP or PTC portable and relatively inexpensive. The tomy, stone extraction, dilatation, stent if therapeutic intervention is major disadvantages are that it is oper- placement) can be performed during the • unlikely to be required ator dependent and the images may be same session. The rates of morbidity and difficult to interpret in obese patients mortality with ERCP from untoward • as a first imaging test when there is a orin those with overlying bowel gas. events such as respiratory depression, previous biliary-enteric or Billroth II 9,10 Also, dilatation of the common bile aspiration, bleeding, perforatio n, anastomosis . duct,which usually indicates biliary cholangitis and are 3% and MRCP has a 95% sensitivity for tractobstruction, is often present in 0.2%, respectively 7. A final consideration detecting obstructi on, though it is

288 Clinical Medicine Vol 1No 4 July/August 2001 CME General Internal Medicine for the Physician – II inaccurate in assessing the grade of Confirmation of these diagnoses, as 4Sorbi D, Boynton J, Lindor KD. The ratio of obstruction 11,12. Similarly, stricture s well as elucidation of diagnoses not aspartate aminotransfer ase to alanine cannot be well characterised due to a revealed by serologic analysis, may be aminotransferase: potential value in differ- entiating nonalcoholic steatohepatitis from signal drop out. Its accuracy is equal to made by liver biopsy. alcoholic liver disease. Am J Gastroenterol that of ERCP in determining both the 1999;94:1018–22. 5Barloon TJ, Bergus GR, Weissman AM. level of obstruction and whether the Liver biopsy obstruction is due to a neoplastic Diagnostic imaging to identify the cause of 54 process10. Unlike ERCP or PTC, MRCP Liver biopsy provides information about jaundice. Am Fam Physician 1996; : 556–62. enables the biliary tree to be visualised hepatic and lobular archi- 6Parsanen PA, Partanen KP, Pikkarainen PH, above and below a complete obstruction. tecture. It is most helpful in undiagnosed Alhava FM et al. A comparison of ultra- It has an advantage over ERCP in persistent jaundice and to stage the sound, computed tomography and endo- being non-interventional, non-operator chronic liver disease. With special scopic retrograde cholangiopanc reat- dependent, and does not require con- histologic features, special stains and/or ography in the differential diagnosis of benign and malignant jaundice and trast injection although, unlike ERCP, it quantification of copper or iron content, cholestasis. Eur J Surg 1993;159:20–9. is purely diagnostic. MRCP has already it permits the diagnosis of a number of 7Cotton PB. Critical appraisal of therapeutic replaced direct cholangiography in many liver diseases, including: endoscopy in biliary tract diseases. Review. 41 clinical circumstances, but ERCP and viral and alcoholic hepatitis Annu Rev Med 1990; :211–22. PTC remain the tests of choice when a • 8Taourel P , Bret PM, Reinhold C, Barkun Wilson’s disease AN, Atri M. Anatomic variants of the bil- therapeutic intervention is necessary. • haemochromatosis iary tree: diagnosis with MR cholangiopan- • creatography. Radiology 1996;199:521–7. alpha 1-antitrypsin deficiency 9Barish MA, Soto JA. MR cholangiopan- Further studies • • fatty liver of pregnancy creatography: techniques and clinical Serologic testing PBC applications. Review. Am J Roentgenol 1997; • 169:1295–303. granulomatous hepatitis When imaging studies do not suggest • 10 Soto JA, Barish MA, Yucel EK, Siegenberg neoplasms. D, et al. Magnetic resonance cholangio- biliary obstructi on, evaluation for • graphy: comparison with endoscopic underlying liver disease must be under- Liver biopsy carries a small complica- retrograde cholangiopancr eatography. taken in jaundiced patients with bio- tion rate, predominantly from bleeding 1996;110:589–97. chemical evidence of hepatocellular and perforation, with morbidity 11 Guibaud L, Bret PM, Reinhold C, Atri M, dysfunction or cholestasis. Appropriate less than 0.5% and a mortality of Barkun AN. Bile duct obstruction and choledocholithiasis: diagnosis with MR 13 screening includes: 0.017% . cholangiography. Radiology 1995;197: • viral serologic testing (for hepatitis 109–15. A, B and C) 12 Morimoto K, Shimoi M, Shirakawa T, Aoki References Y, et al. Biliary obstruction: evaluation with serum levels of iron, transferrin and three-dimensional MR cholangiography. • 1Greenberger N. History taking and physical ferritin (for haemochromatosis), Radiology 1992;183:578–80. examination in patients with liver disease. 13 Grant A, Neuberger J. Guidelines on the use caeruloplasmin and copper (for In: Schiff E, Sorrell M, Maddrey WC (eds). of liver biopsy in clinical practice. British Wilson’s disease) Schiff’s diseases of the liver . Philadelphia: Society of Gastroenterology. Gut 1999; antimitochondrial antibodies (for Lippincot-Raven Publishers, 1999:193–204. • 45(Suppl 4):IV1–11. PBC) 2Lidofsky S, Scharschmidt BF. Jaundice. In: Feldman M, Schsrschmidt BF, Sleisenger antinuclear antibodies • MH (eds). Sleisenger and Fordtran’s Address for correspondence: Gastrointestinal and liver disease . • smooth muscle antibody (for Dr Andrew Burroughs, Consultant ) Philadelphia: Saunders, 1998:220–32. 3Cohen JA, Kaplan MM. The SGOT/SGPT Physician and Hepatologist, Royal • alpha 1-antitrypsin (for alpha 1- ratio: an indicator of alcoholic liver disease. Free Hospital, Pond Street, London antitrypsin deficiency). Dig Dis Sci 1979;24:835–8. NW3 2QG

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