Itchy and Scratchy

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.

Key findings:

  • 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:

  1. Rifampicin has been shown to reduce autotaxin levels in vivo.
  2. MARS and nasobiliary drainage do not directly drain autotaxin; their effects on autotaxin must result by eliminating another factor which stimulates autotaxin production.
  3. Autotaxin is likely to be a useful objective biological marker for pruritus and to evaluate potential novel treatments.
  4. 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:

Challenges with primary sclerosing cholangitis | gutsandgrowth

BRICPFIC, and nasobiliary drainage | gutsandgrowth

Additional references:

  • -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)

  1. ABCB11                     PFIC 2, BRIC 2 (BSEP)
  2. ABCB4                       PFIC 3, ICP (MDR3)
  3. CFTR                         CF (CFTR)
  4. ATP8B1                      PFIC1 -Byler’s (FIC1), BRIC, GFC -Greenland Familial
  5. CLDN1                       NISCH (Claudin 1) -neonatal sclerosing cholangitis/icthyosis VPS33B                     ARC syndrome (Vascular protein sorting 33) -arthrogryposis-   renal dysfn-cholestasis, low GGT
  6. AKR1D1                    BAS: Bile acid synthetic defect: neonatal cholestasis with giant cell hepatitis   (5Beta-reductase)
  7. HSD3B7                    BAS (C27-3Beta-HSD)
  8. CYP7BI                     BAS (CYP7BI)
  9. TJP2 (ZO-2)              FHC: Familial hypercholanemia (tight junction protein)
  10. BAAT                        FHC (BAAT)
  11. EPHX1                     FHC (epoxide hydrolase)
  12. JAG1                        Alagille (JAG1) JAG1 is transmembrance cell-surface protein important in   regulating cell fate during embryogenesis
  13. PKHD1                     ARPKD (fibrocystin -important in ciliary function and tubulogenesis)
  14. PRKCSH                  ADPLD (hepatocystin)
  15. ABCC2                     Dubin-Johnson syndrome (MRP2)
  16. CIRH1A                    NAIC -N Amer Indian childhood cirrhosis (Cirhin)
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8 thoughts on “Itchy and Scratchy

  1. Pingback: Learning a lot from ChiLDREN (part 1) | gutsandgrowth

  2. Pingback: Severe Pruritus with Alagille Syndrome | gutsandgrowth

  3. Pingback: Understanding Cholestatic Pruritus | gutsandgrowth

  4. Pingback: “Genetic Testing and the Future of Pediatric Gastroenterology” | gutsandgrowth

  5. Pingback: Clinical Features of Byler Disease | gutsandgrowth

  6. Pingback: Targeted Therapy for PFIC type 2 | gutsandgrowth

  7. Pingback: Hypothyroidism with ATP8B1 Deficiency | gutsandgrowth

  8. Pingback: What Works for Itching? | gutsandgrowth

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