On TV’s “The Simpsons,” “Itchy” is a sadistic blue mouse and “Scratchy” is a hapless black cat (The Itchy & Scratchy Show – Wikipedia, the free encyclopedia, The Simpsons – Itchy and Scratchy – YouTube). In real life being real itchy is not a joke; it is a common problem with cholestatic liver disease. Beneficial treatments for pruritus may be partly due to their effects on serum autotaxin (Hepatology 2012; 56: 1391-1400, editorial 1194).
In this study, blood was drawn from different treatment groups:
- 17 patients receiving colsevelam (a bile acid sequestrant)
- 10 patients receiving MARS (molecular absorbance recirculating system)
- 6 patients receiving rifampicin
- 5 patients receiving nasobiliary drainage
- Also, autotaxin levels were drawn from healthy controls, atopic dermatitis, Hodgkin’s disease (with and without pruritus), uremic patients, and cholestatic patients without pruritus
The most common diagnosis in all of the cholestatic groups was primary biliary cirrhosis; though some patients had primary sclerosing cholangitis, progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis or other liver disorders.
- Serum autotaxin is increased in pruritic cholestatic liver patients but not in other forms of pruritus. In addition, autotaxin is normal in cholestatic patients without pruritus.
- The level of autotaxin correlates closely with the effectiveness of the treatment as gauged by itch intensity
The reasons for pruritus in cholestasis have not been clear. Several theories have been advanced regarding pathogenesis. Specifically, retained bile acids and increased opiate activity have been thought to play a role. More recently, lysophosphatidic acid (LPA) levels have been noted to be elevated in the serum of patients with cholestatic itch. Injection of LPA into mice results in scratching activity. LPA activity is a consequence of autotaxin.
Other important points:
- Rifampicin has been shown to reduce autotaxin levels in vivo.
- MARS and nasobiliary drainage do not directly drain autotaxin; their effects on autotaxin must result by eliminating another factor which stimulates autotaxin production.
- Autotaxin is likely to be a useful objective biological marker for pruritus and to evaluate potential novel treatments.
- Autotaxin elevation can occur in other noncholestatic inflammatory disease in which pruritus is not a feature; thus, the reasons for pruritus are likely multifactorial and not due to a simple causal role for autotaxin.
Related blog entries:
- -J Hepatol 2009; 51: 237-67. EASL practice guidelines on mgt of cholestatic liver disease
- -JPGN 2010; 51: 787. Use of naltrexone in severe pruritus due to cholestasis: 1-2/kg/day. n=4.
- -JPGN 2008; 46: 241. Excellent review. BRIC caused by FIC1 mutations (same as PFIC1). Nasobiliary drainage of bile may be helpful.
- -Hepatology 2007; 45: 666. Use of sertraline (75-100mg; start with 25mg –in adults)
- -Clin Gastro & Hep 2007; 5:776 Use of zoloft for pruritus in cholestasis.
- -Hepatology 2005; 42: 222. summary of cholestasis workshop
- -JPGN 1999; 29: 442. Rifampin treatment for cholestasis. 90% response, 40% complete response. Extrahepatic cases c much better response. No toxicity observed.
- -Clin Liver Dis 2006; 10: 27-53.
Gene: Disorder (protein)
- ABCB11 PFIC 2, BRIC 2 (BSEP)
- ABCB4 PFIC 3, ICP (MDR3)
- CFTR CF (CFTR)
- ATP8B1 PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
- CLDN1 NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis VPS33B ARC syndrome (Vascular protein sorting 33) -arthrogryposis- renal dysfn-cholestasis, low GGT
- AKR1D1 BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis (5Beta-reductase)
- HSD3B7 BAS (C27-3Beta-HSD)
- CYP7BI BAS (CYP7BI)
- TJP2 (ZO-2) FHC: Familial hypercholanemia (tight junction protein)
- BAAT FHC (BAAT)
- EPHX1 FHC (epoxide hydrolase)
- JAG1 Alagille (JAG1) JAG1 is transmembrance cell-surface protein important in regulating cell fate during embryogenesis
- PKHD1 ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
- PRKCSH ADPLD (hepatocystin)
- ABCC2 Dubin-Johnson syndrome (MRP2)
- CIRH1A NAIC -N Amer Indian childhood cirrhosis (Cirhin)