ONLINE EXCLUSIVE

Ignazio Grattagliano, MD; How best to manage Annarosa Floreani, MD; Enzo Ubaldi, MD; Piero Portincasa, MD chronic Italian College of General Practitioners and Primary Care, Florence, Italy (Drs. Here’s how to maximize your use of lab work and Grattagliano and Ubaldi); Department of Surgery, imaging techniques to identify the source of your Oncology, and , University patient’s cholestasis and provide prompt treatment. of Padua, Italy (Dr. Floreani); Section of Internal Medicine, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, Italy (Dr. Portincasa) CASE u PRACTICE studiomedico@grattagliano. A 44-year-old nurse describes persistent fatigue and itching over RECOMMENDATIONS it the last 2 months. She is taking ramipril 5 mg/d for hypertension ❯ Suspect intrahepatic The authors reported no and has a family history of rheumatic disease. Lab tests reveal a cholestasis in a patient potential conflict of interest recurrent moderate elevation of gamma glutamyl-transpeptidase relevant to this article. with pruritus, normal transaminases, and mildly (gGT; 75 U/L) associated with, on some occasions, mild elevation elevated gamma glutamyl- of alanine aminotransferase (ALT) levels (100 U/L) of unknown transpeptidase and alkaline origin. She has no history of virus infection, hepatotoxic phosphatase levels. A medications, or alcohol intake. She is overweight with a body 2 ❯ Use ultrasonography mass index of 28.5 kg/m and a waist circumference of 99 cm as a first-line diagnostic (39 inches). ultrasonography detects an enlarged liver with tool for cholestasis. A diffuse echostructure dishomogeneity, but no signs of or . The patient’s biliary tree is not dilated. Strength of recommendation (SOR) How would you proceed with the care of this patient? A Good-quality patient-oriented evidence B Inconsistent or limited-quality holestasis is characterized by the alteration of flow patient-oriented evidence through any part of the biliary system, from the hepa-  C Consensus, usual practice, tocyte basocellular membrane to the . The opinion, disease-oriented C evidence, case series condition is classified as intrahepatic when the cause is a de- fect of hepatocellular function or obstruction of the biliary tree within the liver. The extrahepatic form includes all conditions obstructing bile flow in the main biliary tract (choledochus, common ). The key to successfully managing cholestasis lies in the early identification of subtle signs and symptoms before serious complications can arise. In the review that follows, we provide guidance for evaluating laboratory and imaging results that are vital to the accurate diagnosis of intrahepatic and extrahepatic cholestasis. We also detail treatment recommendations.

Clues—subtle and otherwise— of cholestasis Clinical features of cholestasis include fatigue and itching all over the skin. The latter likely is caused by induction of

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E9 TABLE 1 What these serum parameters can tell you8 Alkaline phosphatase (ALP) ALP elevation follows accumulation of bile salts within biliary canalicula with a consequent solubili- zation of the enzyme bound to the canalicular membranes. ALP also is present in other tissues (eg, bone, , gut, placenta), meaning that an isolated increase of ALP could be caused by extrahe- patic conditions. The simultaneous elevation of ALP and gGT (0.5-2.5 times the upper normal limit or 60-300 U/L and 19-95 U/L, respectively) strongly suggests a cholestatic condition. Gamma-glutamyltranspeptidase (gGT)

A microsomal enzyme of , gGT is induced by several medications such as barbiturates and cyclosporine, chronic alcohol intake, and cholestasis. An isolated increase of gGT could suggest non- alcoholic , excessive alcohol intake, or hepatotoxic drug use.

Bilirubin is a later indicator of cholestasis. In conditions of biliary obstruction, plasma levels could reach values 30 to 50 times higher than normal levels (≤15 mg/dL). At very high levels (>20 mg/dL), bilirubin is toxic to the and brain.

Suspect the enzyme autotaxin, which produces the ALP levels appear to be associated with more intrahepatic neuronal activator lysophosphatidic acid. aggressive disease and predict risk of liver cholestasis in Retention of pruritogenic substances that transplantation or death in patients with pri- a patient with normally are excreted into bile might contrib- mary biliary cholangitis (PBC).5,6 Lowering chronic itching, ute to pruritus as well.1 , dark urine, ALP levels is associated with improved dis- normal and pale and fatty stools occur with advanced ease outcomes, including transplant-free transaminases, disease. However, a cholestatic condition can survival rates.5,7) and mildly be detected in asymptomatic patients with el- Elevated serum aminotransferase elevated gamma evated biochemical markers. levels (aspartate aminotransferase [AST] glutamyl- ❚ Mildly elevated gGT and/or alkaline >0.5 times the UNL or 17.5 U/L; ALT >0.5 times transpeptidase. phosphatase (ALP) (0.5-2.5 times the up- the UNL or >18 U/L) and bilirubin (>1.1 mg/ per normal limit [UNL] or 19-95 U/L and dL), with predominance of the conjugated 60-300 U/L, respectively2) in the presence of form (TABLE 18), suggest possible cholestasis. normal transaminase levels (<20 U/L) in an In light of such findings, a clinician’s next step asymptomatic patient can indicate chronic should be to distinguish intrahepatic from liver disease. Signs suggestive of significant extrahepatic conditions. (For a detailed list liver disease have been reported in many pa- of the causes of intra- and extrahepatic cho- tients with gGT or ALP elevation with good lestasis, see TABLES 24 and 3.9) sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.3 How- Patient’s history can provide ever, because abnormal gGT values are com- important clues mon and often resolve spontaneously, family A thorough patient history is especially im- physicians (FPs) may pay little attention to portant when cholestasis is suspected. Details this finding, thus missing an opportunity for about the patient’s occupation, environment, early identification and treatment. and lifestyle are key, as are the specifics of That’s why it’s important to schedule prescribed or over-the-counter medications follow-up testing within 6 months for asymp- and supplements that could be hepatotoxic tomatic patients with abnormal laboratory (TABLE 410). A number of exogenous sub- findings. Persistent elevation of gGT alone or stances can cause liver injury, and the use of accompanied by ALP and ALT elevation (ALT some herbal products (senna, black cohosh, >0.5 times the UNL or >18 U/L) is the most greater celandine, kava) have been linked to common feature of a chronic (>6 months) hepatitis and cholestasis.11 Ask patients about cholestatic condition.4 (In particular, elevated alcohol use and history of conditions associ-

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TABLE 2 TABLE 3 Causes of intrahepatic Causes of extrahepatic cholestasis in adults4 cholestasis in adults9 Hepatocellular causes Intraductal causes Alcoholic and nonalcoholic Benign obstruction: Post-surgical, post- traumatic, biliary stones Amyloidosis, sarcoidosis Choledocholithiasis Hepatic cirrhosis Infections: Tuberculosis Medications (See TABLE 4) Malignant obstruction: , Paraneoplastic syndromes cancer of ampulla of Vater Parenteral nutrition Parasites: Ascaris Secondary cancers Primary sclerosing cholangitis Vascular conditions: Budd-Chiari syndrome, Extraductal causes congestive heart failure Chronic hypertrophic with cholestatic features Enlargement of lymph nodes in the hilum Cholangiocyte causes Mirizzi syndrome (biliary stone wedged in the Anatomical alterations: Caroli syndrome ) Abdominal Cystic fibrosis ultrasonography Graft-versus-host disease Secondary neoplasms from gastrointestinal is a first-line IgG4-associated cholangitis cancers diagnostic tool for cholestasis. Intrahepatic cholestasis during pregnancy Medications ization of an enlarged choledochus (>7 mm) Primary biliary cholangitis or (>5 mm) and an Primary sclerosing cholangitis intrahepatic bile duct diameter that is more than 40% larger than adjacent branches of Sclerosing cholangitis secondary to infections the portal .13 However, ultrasonography (AIDS) or ischemia (vasculitis) has a low diagnostic sensitivity for many con- AIDS, acquired immune deficiency syndrome. ditions (eg, 15% to 89% for detecting stones),14 requiring other diagnostic ated with liver disease, such as diabetes, hy- procedures, such as endoscopic retrograde perlipidemia, and thyroid disorders. cholangiopancreatography (ERCP) or mag- netic resonance cholangiopancreatography Indicators pointing to cholestasis? (MRCP), before reaching a diagnosis. It’s time for ultrasonography ❚ For asymptomatic patients with cir- While biopsy is considered the gold standard rhosis or those at an early stage of liver for diagnosing and staging chronic cholestatic disease, ultrasound at 6-month intervals liver disease and can exclude an extrahepatic combined with serum can obstruction, it should be employed only if be useful to track disease progression and blood tests have been confirmed, second- screen for or chol- level tests have been performed, and ultra- angiocarcinoma.15,16 sound is inconclusive.12 (More on biopsy in ❚ New noninvasive methods. Nonin- a bit.) vasive tools for evaluating the presence and ❚ Ultrasonography is a low-cost, widely severity of liver fibrosis and for differentiating available, noninvasive test that allows easy cirrhosis from noncirrhotic conditions have identification of extrahepatic dilatation of positive predictive values >85% to 90% for the biliary tree and sometimes the underly- some chronic liver diseases.17 Transient elas- ing cause, as well. Ultrasonography identifies tography, which assesses liver stiffness, is one extrahepatic cholestasis by allowing visual- such method. Although it is often used suc-

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E11 TABLE 4 lobular bile ducts leads to signs and symp- Medications that can cause toms of cholestasis and eventually results in 10 cirrhosis and . cholestasis ❚ AMA serum levels show high sensi- Ampicillin and other penicillin-based antibiotics tivity and specificity (90% and 95%, respec- Anabolic steroids tively) for PBC.21 Some PBC patients (<5%) Candesartan cilexetil show histologic confirmation of the disease, but have negative AMA tests (AMA negative Chlorpromazine PBC or autoimmune cholangitis).22 There- Cimetidine fore, according to the American Association Ciprofibrate for the Study of Liver Diseases, diagnosis of Cyclosporin A PBC is guided by the combination of sero- logic, biochemical, and histologic criteria.23 Erythromycin Many PBC patients with or without a posi- Estradiol 17-beta-D-glucuronide tive AMA (≥1:40) also have positive circulat- Gemcitabine ing antinuclear antibodies (ANA; ≥1:80). The Gold salts recent availability of lab tests for antibodies (anti-M2, anti-gp120, anti-sp100) has al- Imipramine lowed identification of subgroups of patients Alkaline Metformin who have a more aggressive form of PBC. Pa- phosphatase Nitrofurantoin tients with PBC often have elevated levels of levels are useful Oral contraceptives circulating IgM (>280 mg/dL). ❚ for monitoring Prochlorperazine Other circulating antibodies can help evolution of discriminate among cholestatic disorders. In Sulindac primary biliary particular, positive tests for perinuclear anti- cholangitis Tenoxicam neutrophil cytoplasmic antibodies (pANCA) disease. Ticlopidine are found in 25% to 95% of patients with pri- Tolbutamide mary sclerosing cholangitis (PSC), a chronic progressive disorder of unknown etiology that is characterized by inflammation, fibro- cessfully, morbid obesity, small intercostal sis, and stricturing of medium and large ducts spaces, and ascites limit its diagnostic capa- of the intrahepatic and extrahepatic biliary bility.18 Recently, some questions about the tree.24 Anti-smooth muscle antibodies (SMA) validity of elastography to assess the extent can be observed in both PSC and autoim- of fibrosis in patients with chronic cholestatic mune hepatitis. conditions have been reported.19,20 Finally, there are syndromes with sero- logic and histologic overlap that are charac- terized by the simultaneous presence of PBC Suspect intrahepatic cholestasis? with or PSC or overlap Your next steps of PSC with autoimmune hepatitis. If imaging techniques do not show bile duct obstruction and you suspect the intrahe- Liver biopsy fills in patic form, second-level tests could have the rest of the diagnostic picture strategic importance. This is where anti- Unfortunately, blood tests reveal little about mitochondrial antibodies (AMAs) come integrity and are not useful for disease in. AMAs are immunoglobulins (IgG and staging. The decision to perform a liver biopsy IgM) directed against mitochondrial an- should be based on several factors, includ- tigens. They are important markers for ing the patient’s age, serum parameters, the PBC, which is a T-lymphocyte-mediated need to stage the disease, therapy choices, attack on small intralobular bile ducts result- and prognosis.12 One should also consider ing in their gradual destruction and eventual that biopsy is a costly procedure with poten- disappearance. The sustained loss of intra- tially serious adverse effects; it should not be

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repeated frequently. However, when a biopsy dosage (15-20 mg/kg/d) is used to facilitate is done, it provides critical information, in- long-lasting biochemical remission. These cluding damage to medium-sized intrahe- patients also need to be monitored for in- patic bile ducts with neoductular formation flammatory bowel diseases, which affect up or bile duct scars and strictures. to 75% of patients,30 and for cholangiocarci- noma, which is a life-limiting complication Treating intrahepatic cholestasis because of a lack of therapy options. Finally, Although FPs often can provide most—or these patients might need endoscopic- even all—of the care for patients with stable guided dilatation of the biliary tree when they conditions, a specialist consultation might have evidence of dominant fibrotic strictures recommend further testing to identify the un- of the greater bile ducts.14,31 derlying disease, which is essential to estab- lish the most appropriate treatment. Addressing the systemic effects ❚ Treatment of patients with PBC is of intrahepatic cholestasis based on administering hydrophilic second- Pruritus. A number of potential pruritogens, ary bile salt ursodeoxycholic acid (UDCA) including bile salts, endogenous opioids, his- 15 mg/kg/d, which is used to equilibrate the tamine, serotonin, and lisophosphatidic acid ratio between hydrophilic and hydrophobic (LPA), can be targeted to relieve pruritus. bile salts in the liver and bile,25 and is the only • resin binders such as cho- treatment approved by the US Food and Drug lestyramine are the first step for treat- Despite progress Administration (FDA) for PBC.4 Taurourso- ing pruritus. UDCA also can be useful, in diagnostic deoxycholate is better absorbed than UDCA, mainly for intrahepatic cholestasis dur- techniques, life and, although partially deconjugated and ing pregnancy. Rifampicin, 300 mg/d, expectancy and reconjugated with glycine, it undergoes re- improves cholestatic pruritus, but is quality of life duced biotransformation to more hydropho- associated with hepatotoxicity and a for patients with bic metabolites and has benefits, including number of severe reactions, such as advanced antioxidant, immunomodulation, and neu- , loss of appetite, hemolytic cholestatic roprotective effects over UDCA—especially anemia, and thrombocytopenia.31 conditions for long-term therapy in PBC.26 However, it is • Most evidence favors a role for remain poor. not used often in clinical practice. opioids in relieving itch, and micro- Bile acid administration counters the opioid receptor antagonists (naltrex- cytotoxic effect of hydrophobic bile salts. Al- one, naloxone, nalmefene) that exert though it seems that UDCA might improve an antipruritic effect can be effective. biochemical and histologic features of the • Sertraline (a selective serotonin reup- disease at earlier stages (I-II), it fails in pa- take inhibitor), 50 to 75 mg/d, usu- tients with more advanced disease.27 In ad- ally is well tolerated in patients with dition, monitoring and defining response to chronic cholestasis and exerts a ben- UDCA is inconsistent, partly because of vari- eficial effect on pruritus in approxi- ations in guideline criteria.28,29 mately 40% of patients.32 Recently a new molecule, obeticholic • Extracorporeal albumin dialysis re- acid (OCA), has been approved by the FDA. moves albumin-bound pruritogens and A farnesoid X receptor agonist, OCA is indi- has been found to be effective in pa- cated for treating patients who do not tolerate tients with liver failure. Steroids and UV UDCA or as an adjunct to UDCA in those with light also can be used in select patients. a partial response to UDCA, defined as low- • The potent neuronal activator LPA ering ALP levels by <1.5 times the baseline and its converting enzyme autotaxin value after 12 months of treatment. have been identified in the serum of ❚ Treating PSC is more complex. Com- patients with cholestatic pruritus; bination therapy with prednisone and experimental modalities using LPA azathioprine is recommended only when antagonists are ongoing for treat- there is an overlap syndrome between PSC ing pruritus in patients who do not and autoimmune hepatitis.4 UDCA at a high respond to other medications.33 CONTINUED

MDEDGE.COM/JFPONLINE VOL 67, NO 7 | JULY 2018 | THE JOURNAL OF FAMILY PRACTICE E13 ❚ Malnutrition. Many patients with cho- ❚ Endoscopic ultrasonography, which lestasis are at risk for malnutrition, which uses an ultrasonographic probe, allows clini- can be exacerbated in those with cirrhosis. cians to evaluate the integrity of the biliary Causes of malnutrition include poor oral in- and pancreatic ducts and is effective for di- take, , or dental problems that agnosing and staging cancer of the ampulla prevent the patient from chewing. Assess of Vater (sensitivity 93% vs 7% for abdominal the nutritional status of every patient with ultrasonography and 29% for CT), and identi- chronic cholestasis, and stress the impor- fying biliary stones and biliary tree strictures. tance of multivitamin supplementation ❚ ERCP is widely employed for diagnosing to reverse systemic alterations caused by and treating pancreatobiliary diseases; how- malnutrition.34 ever, its use has dropped over the last 10 years because of the risk of complications. ERCP is When the patient has nearly exclusively used as a therapeutic pro- advanced disease cedure for pancreatic sphincterotomy, bili- Despite progress in diagnostic techniques, ary dilatations, and removing biliary stones. life expectancy and quality of life for patients It also has a diagnostic role in dominant ste- with advanced cholestatic conditions remain nosis or suspected biliary malignancy using poor. Patients routinely experience fatigue, brushing cytology and sampling biopsies of pruritus, and complications of cirrhosis in- the bile ducts. ERCP is widely cluding ascites, encephalopathy, and bleed- employed for ing. Cholestasis also carries the risk of Treating extrahepatic cholestasis diagnosing life-threatening complications, partly be- Treatment of the different underlying con- and treating cause of comorbidities such as osteoporosis ditions that cause extrahepatic cholestasis pancreatobiliary and malabsorption. is surgical. Thus, the potential surgical tech- diseases; can improve the niques that can resolve or improve an extra- however, its use life expectancy of patients with advanced dis- hepatic cholestatic condition are guided by has dropped ease, but because of long waiting lists, candi- the surgeon and beyond the scope of this over the last dates for transplant often die before an organ article. 10 years because becomes available. For many patients who of the risk of are not in end-stage condition, targeted ther- Treating osteopenia: A concern for intra- complications. apy is crucial to slow disease progression and and extrahepatic cholestasis is recommended along with hepatitis A and Vitamin D deficiency as a consequence of re- B vaccinations and nutritional counseling.35 duced intestinal absorption (poor availability of bile salts) or decreased hepatic activation to 25,OH-cholecalcipherol in both intrahepatic Extrahepatic cholestasis is and extrahepatic cholestasis can lead to re- suspected? How to proceed duced bone formation.39 However, osteopenia Computer tomography (CT) is recom- can occur even in early stages of the disease. mended for better identification of neoplastic Prescribing bisphosphonates, in combination

causes of biliary obstruction and for staging with calcium and vitamin D3, to improve bone purposes. MRCP is an excellent noninva- mineral density is a good practice.40 sive imaging technique for evaluating biliary ducts.36 CASE u ❚ MRCP has 92% to 93% sensitivity and Blood tests and ultrasound imaging sug- 97% to 98% specificity for diagnosing biliary gest the presence of a chronic liver disease. duct stones.37 MRCP also is the first-choice Other lab tests indicate that the patient has modality for evaluating bile ducts in patients an ALP level 3 times normal. This finding, with suspected PSC. If performed in expert together with the other tests, points to a likely centers, the diagnostic accuracy reaches that diagnosis of intrahepatic cholestatic liver dis- of ERCP. A meta-analysis of studies from 2000 ease. Serology confirms positivity for ANA to 2006 has shown a sensitivity of 86% and (1:160) and AMA (1:640). The clinician sus- specificity of 94% for diagnosing PSC.38 pects PBC, so the patient is referred to a liver

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specialist for further evaluation and to deter- transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic . Gastroenterology. mine whether a liver biopsy is needed. 2005;128:343-350. The liver specialist confirms the diagnosis 19. Van Gossum A, Pironi L, Messing B, et al. Transient elastography (FibroScan) is not correlated with liver fibrosis but with cholesta- of PBC, performs a transient elastographym, sis in patients with long-term home parenteral nutrition. JPEN. which indicates a low-grade liver fibrosis 2015;39:719-724. 20. Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholesta- (F1 out of 4), and starts therapy with UDCA. JFP sis increases liver stiffness (FibroScan) irrespective of fibrosis. . 2008;48:1718-1723. CORRESPONDENCE 21. European Association for the Study of the Liver. EASL clinical Ignazio Grattagliano, MD, Italian College of General Prac- practice guidelines: the diagnosis and management of patients titioners and Primary Care, Via del Sansovino 179, 50142, with primary biliary cholangitis. J Hepatol. 2017;67:145-172. Florence, Italy; [email protected]. 22. Ozaslan E, Efe C, Gokbulut Ozaslan N. The diagnosis of antimito- chondrial antibody-negative primary biliary cholangitis. Clin Res Hepatol Gastroenterol. 2016;40:553-561. 23. Lindor KD, Gershwin ME, Poupon R, et al; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. REFERENCES 2009;50:291-308. 1. Kremer AE, Namer B, Bolier R, et al. Pathogenesis and manage- 24. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary scle- ment of pruritus in PBC and PSC. Dig Dis. 2015;33(suppl 2):164- rosing cholangitis. World J Gastroenterol. 2008;14:3781-3791. 175. 25. Dilger K, Hohenester S, Winkler-Budenhofer U, et al. Effect of ur- 2. Deska Pagana K, Pagana TJ. 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