Outcomes and Risk Factors in Cystic Fibrosis Liver Disease

A recent retrospective study (P-Y Boelle et al. Hepatology 2019; 69: 1648-56, associated editorial 1379-81) examines a large cohort of 3,328 patients with cystic fibrosis and pancreatic insufficiency (born after 1985) who were followed into a longitudinal “French CF Modifier Gene Study.”

Background from editorial:

  • Cystic fibrosis liver disease (CFLD) has been thought to occur mainly before puberty with ~40% of patients developing biochemical or ultrasonographic signs of liver involvement by age 12 years.
  • Registry studies have shown slow progression of liver disease with the development of cirrhosis and portal hypertension in 5-10% of patients.  Due to difficulty identifying those at high risk for disease progression and the long time course, it has been impractical to complete definitive clinical trials to establish whether any therapies alter the natural history.
  • Ursodeoxycholic acid (UDCA) is the only current treatment available for CFLD; UDCA has been shown to have beneficial effects on biochemistries and liver stiffness, but effects on survival or need for transplantation are unknown.
  • Concerns have been raised about the potential for toxic UDCA metabolites (eg. lithocholic acid) in part based on unfavorable results of high-dose UDCA with primary sclerosing cholangitis

Key findings of this current study:

  • The incidence of CFLD increased “by approximately 1% every year, reaching 32.2% by age 25”
  • The incidence of severe CFLD increased “only after age 5, reaching 10% by age 30.”
  • Risk factors for CFLD and severe CFLD: male sex, CFTR F508del homozygosity, and history of meconium ileus.
  • Earlier introduction of UDCA (over the last 20 years) “did not change the incidence of severe CFLD.”

My take: This study confirms a previous study showing that CFLD occurs also in adulthood (Koh C et al. Hepatology 2017; 66:591-601) and adds further doubt about whether UDCA is beneficial.

Related article: AJ Freeman et al. “A Multidisciplinary Approach to Pretransplant and Posttransplant Management of Cystic Fibrosis-Associated Liver Disease” Liver Transplantation 2019; 25: 640-57.

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Peonie in Sandy Springs

Ursodeoxycholic Acid, Cystic Fibrosis, and the Problem with Surrogate Markers

A recent study (C Colombo et al. J Pediatr 2016; 177: 59-65) examined 20 patients with cystic fibrosis-associated liver disease (CFLD) who were receiving ursodeoxycholic acid (UDCA) for at least 2 years.  Specifically, they wanted to focus on the extent of biotransformation of UDCA to its hepatotoxic metabolite, lithocholic acid.  The possibility that long-term UDCA therapy could be detrimental was propelled by a primary sclerosing cholangitis study (K Lindor et al. Hepatology 2009; 50: 808) which indicated that high doses of UDCA resulted in worse outcomes despite better “liver function tests.”

Dosing of UDCA: 20 mg/kg/day

Key findings: UDCA became the predominant serum bile acid; 2 hours after UDCA administration, “both UDA and chenodeoxycholic acid significantly increase (P< .01), but no significant changes in serum lithocholic acid concentrations were observed.”

What does this study prove?

Well, not very much.  There are other potential mechanisms for UDCA toxicity and as the editorial notes, “we still lack the necessary endpoints in CF liver disease with which to assess the efficacy of UDCA or any therapy that is on the horizon.”

My take: Because our surrogate markers are unreliable for CFLD, there really is no way to know with certainty whether UDCA therapy is beneficial.


In brief: Pediatric HCV trial, Exercise for NAFLD, and Urso for Unconjugated Hyperbilirubinemia

Schwarz et al. JPGN 2016; 62: 93-96.  This study showed that all 21 children who had achieved a sustained virological response with PEG-interferon/ribavirin maintained an SVR during followup of 4.4-7.0 years.  Hopefully, new direct-acting highly effective oral agents will be approved in pediatrics and make this study less relevant.

U.S. Food and Drug Administration approved Zepatier (elbasvir and grazoprevir) Jan 28, 2016

Anderson et al. JPGN 2016; 62: 110-17.  Participants (n=2612) from a large longitudinal study with prospectively collected data were followed. “The adolescents who are more active in late childhood have lower risk of ultrasound scan fatty liver and lower ϒ-gluamyl transferase levels.”  In addition, they showed that more activity was correlated with lower fat mass in adolescence.

Saki et al. JPGN 2016; 62: 97-100. In a double-blind randomized clinical trial of 80 neonates with unconjugated hyperbilirubinemia, treatment with added ursodeoxycholic acid (5 mg/kg/dose BID) resulted in improved clearance of bilirubin compared to phototherapy alone. At 12, 24 and 48 hours, total bilirubin in the treatment group was 12, 10 and 9.8 respectively compared with 14.4, 12.5, and 10.1 for the control group.  Furthermore, the mean time for phototherapy to decrease bilirubin to <10 was 15.5 hours in the treatment group compared with 44.6 hours in the control group.  This study, if confirmed, could result in shorter hospital stays.

Old Town, San Juan

Old Town, San Juan

Targeted Therapy for PFIC type 2

Progressive Familial Intrahepatic Cholestasis, type 2, (PFIC2) is due to decrease (or absent) function of the bile salt export pump (BSEP) encoded by ABCB11 has been treated mainly in a symptomatic manner with medicines like ursodeoxycholic acid and sometimes biliary diversion.  PFIC2 has been associated with increased risk for hepatocellular carcinoma (HCC).

A recent study (E Gonzales, et al. Hepatology 2015; 62: 558-66) indicates that newer therapies targeting the specific mutation may be effective.

In this study, treatment with oral 4-phenylbutyrate (4-PB) in four patients improved pruritus, serum bile acid concentrations, and liver function tests. 4-PB is considered a chaperone drug and may partially correct mistrafficking.

The associated editorial (pg 349-50) notes that 4-PB has an unpleasant taste and requires ingestion of a large number of pills. In addition, patients with complete loss of BSEP, 4-PB will not be effective. Finally, even in patients with a clinical response, it is unclear if this will lower the risk of HCC.

A second study (S Varma et al. Hepatology 2015; 62: 198-206) retrospectively studied 22 children with PFIC2.  “Children with late-onset presentation, lower ALT, and intracellular BSEP expression are likely to respond, at least transiently, to nontransplant treatment.”  Nontransplant treatment in this cohort included ursodeoxycholic acid in 19 (10 mg/kg thrice daily) and partial biliary diversion in 3.  Higher ALT values were considered to be >165 IU/L. Another point in this study: response to treatment can be slow and take many months.

My take: These studies provide useful information about which patients with PFIC2 respond medically and introduce a new therapy, 4-PB.

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Is this really newsworthy? Perhaps next week: man with venomous snakes says they make great pets?

Perhaps next week the story will be: man with venomous snakes says they make great pets?

What is the Role of Ursodeoxycholic Acid in Primary Sclerosing Cholangitis?

While previous studies of ursodeoxycholic acid (UDCA) at high doses (28-30 mg/kg/day) have been shown to have detrimental effects, a number of randomized controlled trials (RCTs) have shown that low-dose UDCA has been associated with biochemical improvements but no differences in endpoints like death, liver transplantation or cholangiocarcinoma.  Given this conflicting information, a new study (Hepatology 2014; 60: 931-40, editorial 785-88) has examined the effects of withdrawal of low-dose UDCA.

In this cohort, the median age was 34 years, “62% were male, 69% had IBD, 19% had cirrhosis, and the baseline UDCA dose was 10-15 mg/kg/day.”

Key findings:

  • “At 3 months, discontinuation of UDCA in patients with PSC causes significant deterioration in liver biochemistry and influences concentrations of bile acid metabolites.”
  • Alkaline phosphatase increased 75.6%, GGT increased 117.9%, bilirubin increased by 50%, aspartate aminotransferase increased by 45.0%, and alanine amiontransferase increased by 63.9%
  • The Mayo Risk Score for PSC (associated with PSC prognosis) also increased 0.5 points from baseline.

Conclusion (from editorial): “there may still be a role for judicious use of UDCA in patients with well-compensated disease.”  A suggested “yet unproven” algorithm for use of UDCA is noted in Figure 1 pg 787 and considers UDCA for patients with alkaline phosphatase >1.5x ULN and/or PSC-associated symptoms like pruritus.  If no clinical improvement within 6 months, then stopping UDCA is recommended.

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Severe Pruritus with Alagille Syndrome

A recent study reviews the King’s College experience for managing pruritus associated with cholestasis in patients with Alagille syndrome (AGS) (JPGN 2013; 57: 149-54).

This retrospective study examined 62 patients (1995-2010). 82% (n=51) had pruritus.  Most common treatments:

  • Ursodeoxycholic acid in 40 patients. 1st line Rx in 31. Efficacy was rated as good in 20% and some efficacy in 67.5%.
  • Rifampicin in 39 patients. 1st line Rx in 8. Efficacy was rated as very good/good in 49% and some efficacy in 46%.
  • Cholestyramine in 18 patients. 1st line Rx in 9. Efficacy was rated as  very good in 17% and some efficacy in 67%.
  • Naltrexone in 14 patients. Efficacy was rated as good in 43% and some efficacy in 36%.
  • Alimemazine in 13 patients
  • Nonsedating antihistamines in 7 patients
  • Ondansetron in 5 patients
  • Phenobarbital in 1 patient.

Despite these medications, pruritus was controlled by medication in 41% (n=21).  16 patients were referred for liver transplantation and 11 of these patients have been transplanted.  These 11 patients make up 55% of those who had permanent resolution of their pruritus.

The authors proposed an algorithm for treatment:

  • 1st line: ursodeoxycholic acid 10-20 mg/kg/day divided in 2 doses or cholestyramine 240 mg/kg/day divided into 3 doses
  • 2nd line: (if needed) Add/substitute rifampicin 5-10 mg/kg/day divided into 2 doses (max 600 mg/day)
  • 3rd line: (if needed) Add/substitute naltrexone 0.25-0.5 mg/kg/day (max 50 mg/day)
  • 4th line: (if needed) Add/substitute ondansetron max 8 mg/day divided into 2 doses per day (or phenobarbital 5-10 mg/kg/day divided into 2 doses.
  • If none of these are helpful, options could include MARS (molecular adsorbent recirculation system), partial external biliary diversion, or liver transplantation.

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Staying current with PSC

A recent article provides a useful review for primary sclerosing cholangitis (PSC) (Clin Gastroenterol Hepatol 2013; 11: 898-907).

This blog has previously discussed PSC (links below); however, the above reference is succinct and covers the key issues.  A couple of points that I found particularly helpful:

Cancer surveillance:

  • Cholangiocarcinoma (CCA): recommends “consider annual imaging (MRCP or Ultrasound) along with serum CA19-9 levels” to monitor for cholangiocarcinoma.  If there is a dominant stricture, proceed with ERCP with brushings. In pediatrics, the age to start screening is less clear, usually not presenting until beyond the late teen years, though CCA has been diagnosed in one case report at 14 years of age (NEJM 2003; 348: 1464).
  • Gallbladder cancer (30-40-fold higher risk than general population): If gallbladder polyp identified that is ≥0.8 cm, recommends cholecystectomy.  If smaller, may also want to remove if normal synthetic function; otherwise repeat imaging in 3-6 months.
  • Colon cancer: colonoscopy every 1-2 years in those with coexistent IBD (70% of patients with PSC have IBD).

Diagnosis: 44-56% of patients are asymptomatic at time of diagnosis, picked up due to abnormal serum liver tests or on cross-sectional imaging.

Small-duct PSC: occurs in the setting of features of PSC (histology, biochemistry) without abnormal cholangiogram.  This represents 11-17% of PSC patients and is difficult to identify in patients without IBD. Over time, 25% will develop large-duct PSC. Small-duct PSC does not appear to result in increased risk of CCA.

Overlap syndrome with autoimmune hepatitis: patients with typical PSC but with 5- to 10-fold aminotransferase elevations should be suspected of having an overlap syndrome and may benefit from treatments directed at autoimmune hepatitis.  Other features often include histology with an interface hepatitis and the presence of auto-antibodies. This situation is more common in children and young adults.

Immunoglobulin G4-Related sclerosing cholangitis: this occurs most commonly in conjunction with autoimmune pancreatitis.  Since steroids can be effective, IgG4 levels should “be tested in all patients with suspected PSC, and, if elevated to consider an evaluation for IgG4-related disease.”

Medical management: “to date, there are no medical therapies that have been proven to alter the natural course of PSC.”  The discussion notes that standard doses of ursodeoxycholic acid (UDCA) may have protective effects against colorectal cancer in patients with coexisting IBD.  Higher doses of UDCA have been associated with a 2-fold risk of increased disease progression. Specific treatments for dominant strictures, pruritus, metabolic bone disease, and malabsorption are discussed.  In patients with cholestasis, monitoring fat-soluble vitamins is important.

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