Managing the Symptoms and Complications of Cholestasis Mark R

Review

Managing the Symptoms and Complications of Cholestasis Mark R. Pedersen, M.D., and Marlyn J. Mayo, M.D.

The complications of cholestatic liver disease affect a This review focuses on the management of the extra- number of extrahepatic organ systems. Although many hepatic complications of cholestatic liver disease: mineral of these, such as mineral bone disease, dyslipidemia, and bone disease, pruritus, fat-soluble vitamin deficiency, and fat-soluble vitamin deficiency, are found with laboratory dyslipidemia. Special attention will be given to the com- screening, others, such as pruritus, are often found only plementary roles that PCPs and specialists can play in the upon asking. These complications tend to be chronic and evaluation and treatment of these complications and the insidious but are associated with increased morbidity and common pitfalls that can arise. Much of the knowledge mortality. about the complications of cholestasis stems from stud- ies of patients with primary biliary cholangitis (PBC) and Patients with unrecognized or previously diagnosed primary sclerosing cholangitis (PSC). Although several ref- cholestatic liver disease may present to a variety of medical erences in this review are based in this population, their providers for evaluation. A fracture, for example, may be seen conclusions are thought to generalize to the larger popu- in an emergency department; an abnormal lipid panel or pru- lation of patients with various types of chronic cholestatic ritus may be found during a routine annual physical. In all of liver disease. Although fatigue and sicca syndrome are these cases, the underlying pathophysiology could relate to commonly found in patients with cholestasis, cholestasis chronic cholestatic liver disease, which should prompt spe- is unlikely to directly cause sicca syndrome. Thus, the cli- cific evaluation and treatment. Optimal patient care in these nician needs to be aware of the association. Conversely, scenarios depends on the effective communication of clinical the origin of the fatigue is poorly understood and prob- developments between the patient’s primary care physician ably multifactorial, including cholestasis and systemic (PCP) and the treating gastroenterologist or hepatologist. inflammation.

Abbreviations: AASLD, American Association for the Study of Liver Diseases; DEXA, dual energy X-ray absorptiometry; PBC, primary biliary cholangitis; PCP, primary care physician; PSC, primary sclerosing cholangitis. From the Division of Digestive and Liver Disease, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX. Potential conflict of interest: Dr. Mayo advises and received grants from Glaxo Smith Kline and Takeda/Shire. She advises Cara. Received June 13, 2019; accepted October 23, 2019.

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METABOLIC BONE DISEASE for both osteopenia and osteoporosis. Communication with the patient’s PCP can add depth to the decision-making Metabolic bone disease is common in patients with process by revealing important historical features, such as cholestatic liver disease. Only 20% of patients with ad- a history of a fragility fracture of the hip or spine (Fig. 2). vanced PBC or PSC have normal bone density; the re- mainder have osteopenia (t score between −1 and −2.5) Treatment of mineral bone disease is similar to patients or osteoporosis (t score less than −2.5). Of these patients without cholestatic liver disease and can easily be initiated with metabolic bone disease, approximately 25% of them in a PCP’s or specialist’s office. Calcium (1200 mg/day) and will have osteoporosis.1 Bone density initially worsens after vitamin D3 (1000-2000 IU/day cholecalciferol) are advis- liver transplant, particularly in the first 4 to 6 months. able for all patients with cholestatic liver disease in the ab- At 4 months posttransplant, nearly half of patients with sence of renal stones. Vitamin D levels should be targeted cholestatic liver disease will have osteoporosis, and one- to be greater than 30 ng/mL, and higher doses of vitamin third of patients will experience a fracture. Thereafter, for- D (such as 50,000 IU weekly of ergocalciferol for 8 weeks) tunately, bone mineral density starts to improve.2 may be needed for patients who are vitamin D deficient.

Although PCPs are familiar with screening for meta- In patients who meet criteria for osteoporosis, bisphos- bolic bone disease in postmenopausal women, they may phonates should be considered. They have been shown not appreciate that degree to which metabolic bone dis- to improve bone mass and have an acceptable safety pro- ease is a significant complication of cholestatic liver disease. file in patients with PBC, with primary side effects being However, both the American Association for the Study of gastrointestinal.5 Given the large size of the tablets, it is Liver Diseases (AASLD) and the American Association of recommended that patients swallow the tablet with a full Clinical Endocrinologists recommend bone mineral density glass of water, and that they remain upright for 30 minutes testing for patients with cholestatic liver disease every 1 to afterward. Intravenous bisphosphonates (such as zolen- 2 years depending on the initial results (Fig. 1).3,4 This rep- dronic acid) may be considered in patients who have large resents an opportunity for specialists to engage in preventa- esophageal varices, particularly if they are undergoing tive medicine and educate patients on, screen for, and treat banding procedures or sclerotherapy that may exacerbate

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FIG 1 Management algorithm of mineral bone disease in patients with cholestatic liver disease. General preventative measures include smoking cessation, limiting alcohol intake to no more than two standard-size drinks per day, and maintaining an active lifestyle with weight-bearing, balance, and resistance exercises.

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disease.6 Although some patients may present with exco- riations, often the presence of pruritus is discovered only on interview. Pruritus can markedly decrease a patient’s quality of life by affecting mood, concentration, sleep, work ability, and appetite. Cholestatic pruritus has a predilection for the palms and soles, and it has a diurnal variation in intensity, with more severe itching at night (Fig. 3).

Pruritus can be associated with a number of medical conditions, cholestatic liver disease being one of these, and presentation may initially be to a PCP. It is important to eval- uate for concomitant dermatological conditions, renal fail- ure, diabetes, thyroid disorders, hematological disorders, and any underlying psychiatric condition. Even dry skin in the winter, which can be easily treated with topical mois- turizers prescribed by a PCP, can be enough for a patient to report pruritus.6 Communication between the PCP and the specialist can bring the symptom to the attention of the specialist and avoid duplication of the medical evaluation.

Although there is no universally effective treatment for FIG 2 L1 spinal fracture in a patient with cholestatic liver disease. pruritus from cholestatic liver disease, many treatment op- tions exist. Prior to initiation of treatment, assessment with a scale such as a visual analogue scale or the 5-D itch scale pill-associated dysphagia. If the prescribing of bisphospho- (measuring degree, duration, direction, disability, and dis- nates is outside the routine scope of practice of the spe- ruption) can be useful to assess response to treatment.7 cialists, the PCP may represent a convenient alternative to Treatment is often sequential and tailored by the specialist to an endocrinologist for the initiation of therapy. side effect profiles that patients will find acceptable (Table 1). Guidelines from the AASLD are similar to those from the 4 PRURITUS European Association for the Study of the Liver. Although commonly used, antihistamines such as hydroxyzine are not Upward of 80% of patients with cholestatic liver disease thought to be effective for pruritus of cholestasis (other than suffer from pruritus at some point during the course of their to provide a sedating effect, which may help with sleeping).

FIG 3 Prominent excoriation on the soles of the feet of a patient with cholestatic liver disease.

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TABLE 1. DOSAGES AND SIDE EFFECTS OF MEDICATIONS COMMONLY USED FOR CHOLESTATIC PRURITUS

Medication Daily Dosage Side Effects

Cholestyramine 4-16 g in divided Primarily gastrointestinal, with bloating, constipation, and unpleasant taste; affects the intestinal absorption of other medica- doses tions and should not be taken within 2 hours of other medications Rifampin 150-600 mg Rash, fever, nausea, vomiting, and elevated liver enzymes; many drug-drug interactions (such as with warfarin, digitoxin, and tacrolimus) via cytochrome induction Naltrexone 25-50 mg Nausea, dizziness, flushing, drowsiness, and muscles cramps; should not be used for patients who are taking chronic narcotics Sertraline 75-100 mg Side effects include irritability, insomnia, and decreased libido; carries a black box warning for increased risk in adolescents with major depressive disorder

The most common first-line treatment is bile acid binding resins such as cholestyramine or colestipol, with side effects of nausea, constipation, and potential adsorption of other medications taken at the same time. Other medical treatments (and side effects) include the antibiotic rifampin (side effects include fever, rash, elevated liver enzymes, and cytochrome p450 drug-drug interactions), the opioid antagonist naloxone (side effects include opioid withdrawal, nausea, dizziness, and muscle cramps), and the selective serotonin re- uptake inhibitor sertraline (side effects include increase in sui- cidal thinking, insomnia, irritability, diarrhea, and decreased libido). Given the spectrum of side effects of the medications FIG 4 Xanthelasma, which may be seen in patients with and potential for drug-drug interactions, specialists should elevated lipids. Reproduced with permission from Clinical Liver ensure PCPs are aware of the initiation of any of the treat- Disease.12 Copyright 2016, American Association for the Study ments. Although medications are used most commonly to of Liver Diseases. treat pruritus, plasmapheresis and liver transplant might be needed in select patients with intractable disease. considered safe to use in patients with cholestatic liver disease, there can be hesitancy to use these medications in DYSLIPIDEMIA patients with liver disease given their side effect of ele- Patients with cholestatic liver disease frequently have ab- vated liver function tests. In addition, the side effects of normal lipid profiles, which may be discovered on laboratory these drugs, including muscle pain, stomach upset, and results collected as part of a yearly well check with a PCP. headache, can greatly affect a patient’s quality of life. In Patients may also present with yellow plaques around the this instance, the specialist can either directly prescribe eyelid called xanthelasma (Fig. 4) or around palms, soles, the medication or ensure the safety of such medications is and tendons called xanthoma. Approximately 75% of pa- communicated with the PCP. It is important to remember, tients with PBC will have a total cholesterol level greater than however, that the treatment of cholestasis itself can lead 200 mg/day at their first office visit. The cause of dyslipi- to an improvement in dyslipidemia. demia in cholestatic liver disease is an abnormal low-density 8 lipoprotein known as lipoprotein-X. Historically, this dyslipi- FAT-SOLUBLE VITAMIN DEFICIENCY demia has been thought not to be a risk factor for coronary artery disease.9 However, more recent data have suggested Cholestatic liver disease is associated with fat-soluble it may pose a risk, particularly in patients with other risk vitamin deficiency, particularly when the bilirubin starts to factors for coronary artery disease, such as hypertension.10 increase.11 In patients with only mildly elevated or normal bilirubin, other causes of fat-soluble vitamin deficiency There are no specific guidelines for lipid-lowering ther- should be considered, such as celiac disease, small-intesti- apy in patients with cholestatic liver disease; however, nal bacterial overgrowth, and pancreatic insufficiency. guidelines used for the general adult population, such as from the Adult Treatment Panel IV, could be used in Screening for fat-soluble vitamin deficiency (with the this population as well. Although statins and fibrates are exception of vitamin D) is indicated for only a very small

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TABLE 2. laBORATORY DEFINITION, ASSOCIATED SYMPTOMS, AND STANDARD REPLETION OF FAT-SOLUBLE VITAMIN DEFICIENCY

Vitamin Deficient Level Symptoms of Deficiency Dosage for Repletion

Vitamin A (retinol) ≤20 μg/dL Night blindness, follicular dermatitis, 100,000 IU daily for 3 days, then 50,000 IU daily for abnormal teeth, xerosis 2 weeks, then 10,000-20,000 daily for 2 months Vitamin D (25-hydroxyvitamin D) ≤30 ng/mL Rickets, osteomalacia, tetany 50,000 IU weekly of ergocalciferol for 8-12 weeks Vitamin E (α-tocopherol) ≤5 μg/dL Hemolysis, ophthalmoplegia, peripheral 100-400 IU daily of α-tocopherol neuropathy Vitamin K (phytonadione) Prothrombin time >13 seconds Delayed blood clotting and hemorrhage 1-10 mg daily for 1-3 days portion of the general population, and most patients with Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, a fat-soluble vitamin deficiency will not manifest classic TX 75390. E-mail: [email protected] clinical symptoms. Fat-soluble vitamin deficiencies are thus REFERENCES unlikely to be diagnosed at a routine PCP visit, meaning 1) Menon KVN, Angulo P, Weston S, et al. Bone disease in primary that screening and treatment of fat-soluble vitamin de- biliary cirrhosis: independent indicators and rate of progression. ficiency are the primary responsibility of the specialist. J Hepatol 2001;35:316-323. Current recommendations from the AASLD suggest mon- 2) Guichelaar MM, Kendall R, Malinchoc M, et al. Bone mineral density itoring fat-soluble vitamins annually in patients with PBC before and after OLT: long-term follow-up and predictive factors. 4 with a bilirubin greater than 2 mg/dL. The most common Liver Transpl 2006;12:1390-1402. deficiency found is vitamin D deficiency, as discussed ear- 3) Camacho PM, Petak SM, Binkley N, et al. American Association of lier. The common symptoms and treatment of fat-soluble Clinical Endocrinologists and American College of Endocrinology vitamin deficiency are listed in Table 2. clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis—2016. Endocr Pract 2016;22(suppl 4): CONCLUSION 1-42. 4) Lindor KD, Bowlus CL, Boyer J, et al. Primary biliary cholangitis: 2018 The successful management of a patient with cholestatic practice guidance from the American Association for the Study of liver disease addresses not only the liver-specific physiol- Liver Diseases. Hepatology 2019;69:394-419. ogy but also the extrahepatic manifestations of the dis- 5) Guanabens N, Monegal A, Cerda D, et al. Randomized trial com- ease, which can affect quality of life and mortality. Some paring monthly ibandronate and weekly alendronate for oste- of these manifestations, such as pruritus, can be found oporosis in patients with primary biliary cirrhosis. Hepatology by simply asking. PCPs are effective at providing an initial 2013;58:2070-2078. evaluation of the various causes of pruritus. Specialists, 6) Jin XY, Khan TM. Quality of life among patients suffering from however, can elucidate the relationship of pruritus to liver cholestatic liver disease-induced pruritus: a systematic review. disease, which can lead to early use of evidence-based J Formos Med Assoc 2016;115:689-702. treatments. Others complications, such as metabolic bone 7) Elman S, Hynan LS, Gabriel V, et al. The 5-D itch scale: a new mea- disease, fat-soluble vitamin deficiency, and dyslipidemia, sure of pruritus. Br J Dermatol 2010;162:587-593. require proactive screening. PCPs may provide key pieces 8) Soros P, Bottcher J, Maschek H, et al. Lipoprotein-X in patients with of history (history of fragility fractures) or laboratory data cirrhosis: Its relationship to cholestasis and hypercholesterolemia. (abnormal lipid panels). Specialists, however, should proac- Hepatology 1998;28:1199-1205. tively screen for these conditions and provide guidance to 9) Sorokin A, Brown JL, Thompson PD. Primary biliary cirrhosis, hyperlip- PCPs on any specific treatments that may be required (such idemia, and atherosclerotic risk: a systematic review. Atherosclerosis as bisphosphonates or lipid-lowering medications). This 2007;194:293-299. multidisciplinary care hinges on effective communication, 10) Wang C, Zhao P, Liu W. Risk of incident coronary artery dis- which unfortunately is not always easy in our health care ease in patients with primary biliary cirrhosis. Int J Clin Exp Med system. However, both physicians and the patient stand to 2014;7:2921-2924. benefit in this arrangement. 11) Kaplan MM, Elta GH, Furie B, et al. Fat-soluble vitamin nutriture in CORRESPONDENCE primary biliary cirrhosis. Gastroenterology 1988;95:787-792.

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