Help with hepcidin

Posted on by

Over the past several years, the mechanisms involved in iron overload have been carefully examined and the genetic basis for most of these disorders is now understood.  Several review articles on these disorders have been published; the most recent with excellent diagrams is in last week’s NEJM (NEJM 2012; 366: 348-59 & NEJM 2012; 366: 376-77). Although the process is quite complicated, the most important aspect regarding iron homeostasis is a feedback loop involving hepcidin-ferroportin.  Hepcidin functions as a ‘hypoferremia hormone.’  It down regulates ferroportin release of iron into the circulation.  Hepcidin is also an acute-phase protein and inflammation affects its function.

Hepcidin levels fluctuate in response to the body’s iron needs: more hepcidin causes less iron absorption & less hepcidin causes more iron absorption.

  • Iron balance disorders can usually be attributed to altered hepcidin production.
  • Anemia of chronic disease, though multifactorial, is mostly due to increased hepcidin production in response to inflammation.
  • Hemochromatosis results from genetic mutations causing lack of normal hepcidin production.  The severity of these disorders correlates with hepcidin levels.
  • Hepcidin agonists could be used to treat hemochromatosis and other iron overload conditions (eg. thalassemia with transfusion therapy).  For hemochromatosis, phlebotomy will be less expensive.
  • Hepcidin antagonists could treat anemia of chronic disease

Additional references:

  • -Hepatology 2011; 54: 328.  Review.  Guidelines.
  • -Hepatology 2010; 52: 925.  HFE homozygotes, n=31,192 w low risk of clinical symptoms if ferritin <1000.
  • -Gastroenterology 2010; 139: 393. Review –pathogenesis/dx/Rx
  • -Hepatology 2009; 50: 94.  C282Y/H63D compound heterozygotes (n=180) are at low risk for hemochromatosis-related morbidity compared with control group.
  • -Hepatology 2008; 48: 991.  Review.
  • -Hepatology 2007; 46: 960, 1071.  Review of clinical phenotypes.  Of C282Y homozygotes, only 1-2% develop HCC, 6% cirrhosis, 25% liver fibrosis, 38% Fe overload, 61-75% develop raised serum iron indices.
  • -Hepatology 2007; 46: 1291. Review of hemochromatosis
  • -Hepatology 2007; 45: 253. Review of iron metabolism
  • -NEJM 2004; 350: 2383. Review.  Several genetic mutations associated with clinical phenotype.  type 1: Classic HFE, types 2A & 2B: (Juvenile type)  HJV & HAMP (gene products hemojuvelin & hepcidin), type 3:TFR2 (transferrin receptor 2), and type 4:SLC40A1
  • -NEJM 2005; 352: 1011. Algorithm.  If transferrin saturation <16%, check ferritin.  If ferritin less than 30, Fe-deficiency; if >100, anemia of chronic disease.  If 30-100, check soluble transferrin receptor (level of sTranReceptor/log ferritin less than 1 is c/w anemia of chronic disease whereas when this ratio is greater than 2, c/w combined Fe-def anemia and anemia of chronic disease).  Hepcidin is produced by hepatocytes and regulates iron homeostasis.  Hepcidin interacts with ferroportin, an iron export protein on enterocytes (& other cells), & facilitates internalization and degradation of ferroportin.  It may lead to decreased dietary iron absorption and to retention of iron body stores.  Hepcidin expression can be up-regulated by high iron levels or during acute phase inflammatory responses (thus can contribute to anemia of chronic disease).  Hereditary hemochromatosis associated with low hepcidin levels in the face of increased iron body stores.  Several genes can affect hepcidin loss of function, including HFE, hemojuvelin (HJV), and transferrin receptor 2 (TFR2).
  • -Gastroenterology 1996; 110: 1107.  Sentinel article discussing long-term survival in hemochromatosis and role of iron.

More on ethanol locks

Posted on by

In a post earlier this week (Four advances for intestinal failure), ethanol locks were discussed.  More on information this subject (Pediatrics 2012: 129: 318-29) comes in a meta-analysis.  These authors identified 4 retrospective studies in pediatric IF populations.  Ethanol locks reduced infections by 81% and line replacements by 72%.  The studies in this meta-analysis overlapped with the six studies cited in the previous post.  Adverse events were rare and included thrombotic events.

Additional reference:

  • -JPEN 2012; 36: 36S-42S

What is calretinin?

Posted on by

Calretinin is a ‘calcium-binding protein that is normally expressed in cholinergic nerves.’ (NEJM 2012:366: 361-72)  The absence of calretinin-positive mucosal neurites helps establish a diagnosis of Hirschsprung’s disease, even when suction-biopsy specimens may have previously been considered inadequate.  It is not known why calretinin neurites are absent in Hirschsprung’s disease nor why abnormal acetylcholinesterase-positive neurites are present.

More information on the technical aspects of diagnosing Hirschsprung’s disease and illustrations of these stains is available in this case record.

Additional references:

  • -Mod Pathol 2009; 22: 1379-84. Calretinin in Hirschsprung’s.
  • -Pediatr Dev Pathol 2009; 12: 6-15. Calretinin & acetylcholinesterase in Hirschsprung’s.
  • -JPGN 2011; 53: 75.  Problems post-op.
  • -JPGN 2008; 46:13.  Nice review.
  • -Pediatrics 2002; 109: 914-918.  Review of surgical treatments.
  • http://www.ccdhc.org/diseases/Hirschsprung.html

Blood is not enough

Posted on by

…to resolve the problems of sickle cell anemia.  The effects of transfusions for sickle cell patients’ hepatobiliary function are poorly understood.  By lowering the level of hemoglobin S and reducing sickling, can this lead to improvement in organs damaged by sinusoidal congestion and infarction?  Well probably not (J Pediatr 2012; 160: 281-85).

Strokes are known to occur in 5-10% of sickle cell patients by 20 years of age and if untreated, >50% have recurrence.  This has led to transfusion programs.  The ‘Stroke with Transfusions Changing to Hydrdoxyurea’ (SWiTCH) study is a multi-center randomized trial trying to determine how current treatment (transfusions and chelation) compares with hydroxyurea/phlebotomy for preventing stroke and managing iron overload.  As part of this study, a baseline assessment with ultrasound showed widespread problems -despite an average of 7 years of transfusions.  In this cohort of 149 patients, the following findings were identified:

  • Spleen volumes were increased in more than 1/3rd of patients leading to hypersplenism (low platelet counts). 12 subjects had nonvisible spleens due to autoinfarction.
  • Nephromegaly was present.  This finding is known to occur with sickle cell disease and is a marker of glomerular hyperfiltration.
  • Hepatobiliary disease was nearly ubiquitous.  37 of 148 had previous cholecytectomy; of the remaining, 46 of 111 (41%) had gallstones and 14% had gallbladder sludge.  Liver lengths were significantly longer as well.

Conclusions: Transfusion therapy was insufficient to reverse or prevent organ damage in children with sickle cell anemia.  An important limitation– the severity of the underlying prevalence of organ dysfunction prior to initiation of transfusion therapy was not known.

Additional references:

  • -Blood 2011; 117: 772-9.  Silent cerebral infarcts occur despite regular blood transfusions.
  • -Clin Gastro & Hep 2007; 5: 1469.  Reviews types of sickle cell associated liver disease.
  • -Pediatric Hematology and Oncology.  2006 Mar;23(2): 95-102(8).  Sickle cell intrahepatic cholestasis (SCIC), which is related to intrahepatic sinusoidal RBC sickling (due to relative hypoxia) and can be associated with progressive hepatomegaly, mild transaminitis, extreme hyperbilirubinemia
  • -JPGN 2004; 39: 200.  Review of sickle cell hepatic crisis.  Cholestasis resolves over 3 months.  Acute crisis treated with hyperhydration & transfusion. Cohort of 350; 6 developed hepatic crisis.
  • -J Pediatr 2001; 139: 785-789 & 790-796.  Transfusions and hydroxyurea for SS dz.

Four advances for intestinal failure

Posted on by

Several advances in the management of intestinal failure have the potential to improve the outlook for our intestinal failure (IF) (aka Short Bowel Syndrome) patients (JPEN 2012; 36: 36S-42S).

Although IF patients already have improving survival with rates of 80-95% over followup ranging from 1-5 years, many still do not survive, primarily due to bacterial infections or chronic liver disease.  Ongoing research has made some promising steps in the management of these pediatric patients.  This article focuses on four of these steps.

1. Citrulline monitoring

  • Major source of citrulline is enterocyte production.  Citrulline is an amino acid not encoded in human genetic code; it is present in some proteins as a product of posttranslational modification.
  • Watermelon is one of few dietary sources.
  • Useful biomarker for bowel length/absorption –independent of inflammatory markers
  • Levels >15-20 μmol/L indicate good likelihood of achieving enteral autonomy
  • Levels <12μmol/L indicate a very low likelihood of achieving enteral autonomy

2. Teduglutide therapy

  • Analog of glucagon-like peptide 2 (GLP-2) but harder to degrade (longer half-life)
  • Preliminary studies in adults indicate improvement in absorption and villous histology after subcutaneous administration for three weeks.  Improvements reverse when drug is discontinued.
  • Since GLP-2 is produced by colon & increased in IF (if colon present), unclear whether exogenous administration will be as beneficial in patients with residual colon

3. Lipid minimization &/or fish oil lipids

  • Cholestasis increases in patients receiving more than 1 g/kg/day of intralipids (soy based).
  • Fish oil (Omegaven) has shown benefit in lowering cholestasis in numerous case reports.  This may be due the high content of anti-inflammatory ω-3 fatty acids.
  • Another preparation SMOFLipid is a mixed formulation and may be safer than pure fish oil; randomized controlled studies of both of these lipid formulations are underway.
  • Fish oil has not been shown to improve histology
  • Parenteral nutrition associated liver disease (PNALD) may improve with lowering lipids & may not need omegaven

4. Ethanol locks

  • May be beneficial in treating and preventing central line infections.  In both situations, in small studies, ethanol locks lowered incidence of recurrent infections.
  • Six studies involving 75 patients (66 pediatric patients) lowered infection rates from approximately 10 per 1000 catheter days to 2 per 1000 catheter days.
  • Ethanol concentrations were mostly 70% in these studies, though 25% has been used.
  • Dwell times ranged from 2-14 hours.
  • Randomized studies are in progress.
  • Fewer infections should reduce the likelihood of death from sepsis and death due to loss of venous access.

Additional references:

  • -NEJM 2010; 362: 181.  Letter to editor describes use of fish oil in (n=125) Boston pediatric patients.
  • -JPGN 2009; 48: 209. n=12. SBS.9/12 improved with omegaven. 3 had transplant (L-ITx). No controls.
  • -NEJM 2009; 361: 998. Intestinal Rx.  Review claims ~90% 1yr survival. 47% 5yr, 61% 3yr (expecting to go higher)
  • -JPGN 2009; 48: 334. Isolated liver w SBS feasible IF 50cm small bowel remaining or 30cm w ICV, 50% enteral nutrition >4 weeks with good growth, no dysmotility.
  • -Pediatrics 2008; 121: e678. n=18. use of fish oil improved cholestasis compared to historical controls.
  • -Gastroenterology 2008; 135: 61, 303. Survival of ITx (vs. HAL).  In many conditions, better off from survival standpoint without Tx. Tx if failure of TPN (severe liver dz/thrombosis of >/= 2 central veins, multiple bouts of sepsis/frequent dehydration), high risk of death, severe short bowel (<10cm in infants and <20cm in adults), pseudoobstruction, unwillingness to accept long-term tpn. 93% of TPN patients who did not have TPN-complications had 93% survival rate.  Thus, TPN is first line Rx as survival and quality of life often better.
  • -Pediatrics 2006; 118: e197-e201.  Reversal of TPN-AC c IV omega-3 fatty acids (fish oil-derived) instead of intralipids
  • -Liver Transplantation 2006; 12: 1062, 1040. Liver transplant alone reasonable to consider in some SBS patients who tolerate >50% enteral therapy and are less than 2 years old.
  • -Gastroenterology 2006; 130. Supp 1. Summary of NIH workshop on intestinal failure. TX Indications: Liver disease, thrombosis of major veins, recurrent catheter-related sepsis, frequent severe dehydration/electrolyte imbalance.
  • -JPGN 2005; 41: 47A (pg507). Poor prognosis: <40cm, needing >40kcal/kg PN, increased bili (>150 μmol/L)
  • -J Pediatr 2005; 146: 542. Serum citrulline > 19 μ/L associated with bowel adaptation/weaning off HAL.
  • -J Pediatr 2004; 145: 157-163. Survival of SBS with as little as 15
  • -Arch Pediatr Adolesc Med 2006; 160: 104953.  Use of ethanol lock (70%, 08-1.4mL for 12-24hrs, then withdraw). n=51.  High success rate in salvaging line
  • -J Pediatr 2001; 139: 27-33. Review of 30 pts. 3 of 30 pts with bowel length 40cm or less able to wean PN.
  • -Gastroenterology 2001; 120: 806-815. Glucagon-like peptide 2 improves nutrient absorption marginally.

Speed matters

Posted on by

Capsule endoscopy is cool.  Like any technology, it has certain advantages and some shortcomings.  Understanding that this technology has limited sensitivity and specificity is an important matter in clinical practice.

The suboptimal sensitivity is apparent in a recent study (Am J Gastroenterology, (10 January 2012) | doi:10.1038/ajg.2011.461).  In this study titled, “Detection of Lesions During Capsule Endoscopy: Physician Performance Is Disappointing,” the authors compare the performance of 17 capsule endoscopists in reading clips from 24 capsule procedures.  18 of these clips were abnormal but only abnormal in <0.1% of frames.  They compared different reading modes, speeds and the experience of the physicians.  By using clips, they were able to truncate the sessions to a similar length as an individual capsule procedure.

Their findings showed detection rates of 69% for angioectasias, 38% for ulcers/erosions, 46% for masses/polyps, and 17% for blood.  For all categories the detection rate was ~45% for SingleView15, QuadView20, and QuadView30; however, SingleView25 had a 25% detection rate.  One surprising finding was how little experience mattered; there was no significant advantage in having more experience.  In fact, the best performer who correctly identified 78% of the abnormalities had read only 45 capsule studies previously; the worst performer with a 17% score had read more than 11,000 previously.

In a typical capsule study, 40,000-60,000 images are generated.  If there is not a diffuse disease, then the lesion may go undetected.  The findings of these studies, though limited by the small number of interpreting physicians, confirm problems with sensitivity from other studies.  One aspect of this study that deserves emphasis is that speed matters.  As with colonoscopy, additional time reviewing the study does increase the likelihood of identifying abnormalities.  Ultimately, technological innovation may improve the results with capsule endoscopy.  With newer versions of the software,  “suspected blood indicator” (SBI) quickly identified six of the 18 lesions and “QuickView” identified 11 of the 18 lesions.  As with any test, though, if the clinical suspicion is high, having another physician review the study or using an alternative imaging tool may be necessary.

Another problem to keep in mind with capsule endoscopy (or wireless capsule endoscopy -WCE) is that especially in adults there is a significant background abnormality rate that may be clinically unrelated (Clin Gastro & Hepatol 2005; 3: 133-141. n=413. 13.8% with baseline mucosal injury).

Additional references:

  • -IBD 2008; 14: 1219. Correlation of capsule & MRI enteroclysis. Capsule detected more mucosal lesions.
  • -JPGN 2008; 47: 31. Capsule endoscopy may reclassify pediatric IBD.
  • -Dig Liver Dis 2008; 40: 216-223. Study comparing capsule vs EGD in detecting varices.
  • -JPGN 2008; 46:4. Review.
  • -Gastroenterology 2007; 132: 855. Capsule outperforms push enteroscopy.
  • -IBD 2007; 13: 331. Role of WCE in IBD.
  • -Pediatrics 2006; 118: e904. Use of capsule endoscopy for HSP
  • -Clin Gastro & Hep 2005; 3: 959. WCE should be 2nd step in obscure bleed, p egd/col.
  • -Clin Gastro & Hep 2005; 3: 772. WCE outperforms enteroclysis in identifying Crohn’s sm bwl dz.
  • -Gastroenterology 2005; 128: 1172. NSAID injury witnessed in 68% of healthy volunteers p 2 week course; 75% c increased fecal calprotectin.
  • -Clin Gastro & Hepatol 2005; 3: 411. Practical applications & review.
  • -Clin Gastro & Hepatol 2005; 3: 264-70. Study of 30 children; helpful in diagnosing obscure bleeding.
  • -Endoscopy 2005; 37: 960-65. Results of capsule endoscopy trials
  • -Clin Gastro & Hepatol 2005; 3: 133-141. WCE to assess NSAID injury, n=413. 13.8% with baseline mucosal injury. Celebrex with fewer lesions than Naproxen plus omeprazole.
  • -Gortzak Y, Lantsberg L, Odes HS. Video capsule entrapped in a Meckel’s diverticulum. J Clin Gastro 2003; 37: 270-271.
  • -Clin Gastro & Hep 2005; 3: 55. visible lesions c NSAIDs
  • -IBD 2004;10: 278-285. WCE for Crohn’s (review) Capsule can help differentiate UC from Crohn’s.
  • -Clin Gastro & Hepatology 2004; 2:xx. Dx of Peutz-Jeghers w WCE.
  • -Gastro 2004; 126: 643-653. WCE performs well for occult bleeding, especially active bleeding (87% detection rate)
  • -Clinical Gastro & Hepatology 2004; 2: 14-15, 31-40.
  • -Gastroenterology 2003; 124 (suppl 1) A37. abnl small bowel findings common in healthy subjects.
  • -JPGN 2003; 37: 332 (18A), n=58. Crohn’s, polyposis, occult bleeding
  • -Gastroenterology  2003; 124: suppl 1, A-37 (284) 22% of normal pts c abnl wireless findings
  • -Gastroenterology  2002; 123: 999-1005, 1385-88. capsule is superior to radiographs for suspected small bowel dz.
  • -Gastro Endosc 2002; 56: 452-456. Algorithm suggests using this modality if negative upper & lower endoscopy & no acute overt bleeding. If capsule endoscopy is negative & patient is stable, observation appropriate.
  • -Gastro Endosc 2002; 56: 621-24. ASGE guidelines.

Potential and pitfalls of probiotics with necrotizing enterocolitis

Posted on by

Recent developments in necrotizing enterocolitis (NEC) have focused on the potential role of new biomarkers and preventive strategies (JPEN 2012; 36: 30S-35S).  In this report, the clinical/diagnostic features of NEC are reviewed:

  • classic form develops between 29-32 weeks corrected gestational age
  • features include feeding intolerance, abdominal distention, bloody stools
  • imaging features: pneumotosis intestinalis, portal venous gas, paucity of gas, fixed bowel loops
  • full term or late NEC usually occurs in the setting of risk factors like congenital heart disease, exchange transfusions, gastroschisis, and neural tube defects
  • spontaneous intestinal perforation due to glucocorticoids or indomethacin may be confused with NEC.  It usually occurs earlier than NEC

This review describes the potential for new biomarkers, including urinary I-FABP & fecal calprotectin. These assays would need to be available with very short turn-around time given the often rapid development of NEC.

Finally, this articles discusses the evidence for preventive measures.  Human milk has been shown to decrease NEC and gradual introduction of feedings remains important. With regard to microbial colonization, NEC does not occur until at least 8-10 days postpartum coincident with anerobic bacterial colonization of intestinal tract.

This has led to attempts to alter the colonization to decrease NEC incidence. 16 randomized controlled trials with 14 different probiotics have been completed.  Most are underpowered.  “The available trials do not permit a decision to be made with respect to optimum strain, dosing, or protocol.”  In a cautionary note, a preterm pig model demonstrated an increase NEC incidence with the use of a specific probiotic (Pediatr Res 2011; 69: 10-16).  Furthermore, probiotics are plagued by a lack of adequate quality control.

Additional references:

  • -Ann Surg 2010; 251: 1174-80.  Non-invasive biomarkers for NEC.
  • -J Peds 2011; 158: 672-74.  Caution advised with probiotics for NEC.
  • -J Peds 2011; 159: 392. n=124 cases (248 controls). retrospective study suggested that abx exposure is a risk factor for NEC (3-fold risk).  Abx -marker for illness or true predisposing factor?
  • -NEJM 2011; 364: 255-64.  NEC review.
  • -Cochrane Database Syst Rev 2011; 3: CD005496.  Probiotics for NEC.
  • -NEJM 2011; 364: 1877. Probiotics likely helpful in preemies with birth wt >1000gm.
  • -NEJM 2010; 364: 255.
  • -Pediatrics 2010; 125: 921-30.  Meta-analysis of probiotics for NEC.
  • -JPS 2009; 44: 1072-76. Mortalitiy of NEC expressed by birth weight.
  • –Pediatrics 2008; 122: 693-700. Multicenter trial of probiotics in VLBW for NEC prevention.
  • -J Pediatr 2008; 153: 339. Cluster of NEC due to norovirus.
  • -Pediatrics 2007; 119; e164. Rate of 0.4% among large cohort of infants w/o indocin, steroids & w slow delayed feedings.
  • -Pediatrics 2006; 117: e137. H2-blockers associated with increased NEC (?causal)
  • -Pediatrics 2005; 116: 1064. CRP helpful. If CRP was persistently normal, antibiotics were aborted and enteral feeds restarted safely.
  • -Pediatrics 2005; 115: 1-4 & 171 editorial.  Probiotics decreased NEC in this study.
  • -J Pediatr 2003; 143: 543. Images of pneumotosis.

The heart connection

Posted on by

Cardiac changes with biliary atresia (BA) are surprisingly common– Gastoenterology 2011; 141: 1264-72.  In this study, 48 patients with BA, listed for liver transplantation, underwent echocardiography between 2004-2010.  The median age was 8 months.  Significant increases in left ventricle wall thickness (23% increase) and mass (51% increase) were noted; in addition, functional changes were noted as there was an increase in LV shortening fraction (8% increase).  Features of ‘cirrhotic cardiomyopathy’ were evident in 72% of infants (29/40).  The authors conclude that these heart changes likely contribute to prolongation of posttransplant hospitalization.

Additional References:

  • -J Am Coll Cardiol 2010; 56: 539-49
  • -J Hepatol 2010; 53: 179-90.

Add it to the list

Posted on by

A recent review article (NEJM 2012; 366: 158-64) describes a common, chronic recurrent granulomatous inflammatory disease that manifests as painful, deep-seated inflamed lesions (including sinus tracts and abscesses); it typically starts after puberty.  This disease is due in part to aberrant healing processes and impaired mechanical integrity. Investigations have shown that tumor necrosis factor α is involved in the pathogenesis of hidradenitis suppurativa.  There are a lot of similarities between hidradenitis suppurativa and Crohn’s disease as well as some overlap as up to 17% of individuals with Crohn’s disease have hidradenitis suppurativa.  In addition, hidradenitis suppurativa can be confused with Crohn’s disease especially when buttocks/perianal lesions are present.

Key clinical points with this disease:

  • Affects skin with apocrine glands
  • Long delay in diagnosis is common though disorder may affect 1% of population
  • Incision and drainage is not effective treatment –lesions recur
  • Few randomized studies –most often treated with combination of antibiotics (eg. clindamycin & rifampin)
  • More severe disease may benefit from TNF inhibitors or possibly complete surgical excision
For pediatric gastroenterologists, hidradenitis suppurative is another to add to the Crohn’s differential diagnosis list:
 

Infectious etiologies: 

Histoplasma , Amebiasis, CMV, C. diff, Klebsiella oxytoca, Actinomycosis, HIV

Noninfectious etiologies:

Sarcoidosis, Vasculitis (HSP,dermatomyositis, Wegener’s, SLE), FMF, allergic colitis, Hirschsprung’s, autoimmune enteropathy, Chronic granulomatous disease, glycogen storage dz, 1B, Hermansky-Pudlak syndrome, Wiskott Aldrich syndrome, NEMO (NF-kB essential modifier) deficiency, Leukocyte adhesion deficiency, SCID, Behcet’s, FELS/hemophagocytic lymphohistiocytosis, Typhlitis

Additional reference for hidradenitis suppurativa:

  • -Br J Dermatol 2010; 162: 195-7.

Crohn’s Disease and differential diagnosis -references:

  • -JPGN 2010; 51: 690. Discusses sarcoid (check angiotensin converting enzyme), CGD, Hermansky Pudlak
  • -JPGN 2010; 50: 99. Perianal dz in young children may be due to autoimmune neutropenia.
  • -IBD 2008; 14: 1443. Phagocyte dysfunction. Also, discusses Hermansky-Pudlak, GSD 1B, chronic granulomatous disease, Chediak-Higashi, leukocyte adhesion deficiency, cylic neutropenia, congenital neutropenia
  • -JPGN 2006; 42: 405. Vasculitis mimicking IBD.
  • -NEJM 2005; 352: 489-94.
  • -J Clin Gastroenterol 1992; 15: 17-23.
  • -NEJM 2003; 349 (26): 2541-49.  Table 2. (Gold et al.)

Hepatic ciliopathies

Posted on by

As our understanding of pathophysiology improves, frequently this results in reclassification of diseases.  Perhaps the best example in pediatric hepatology is gestational alloimune liver disease/congenital alloimmune hepatitis, formerly called neonatal hemochromatosis  (see previous post).  Hepatic ciliopathies are less commonly discussed and thus far have not resulted in abandoning previous nomenclature. These hepatic ciliopathies are related to fibrocystic disease proteins which localize to the primary cilia.  Ductal plate malformation is the main pathology that underlies the liver disease in ciliopathies.  The characteristics of one of these disorders, congenital hepatic fibrosis (CHF) in autosomal dominant polycystic kidney diseae (PKD) involving 19 patients is described in this month’s JPGN (JPGN 2012: 54: 83-89).  Portal hypertension was the main manifestation.  “Hepatocellular function was preserved and liver enzymes were largely normal.”  In patients with AD-PKD-CHF, this was  due to PKD1 mutations with probable contributions from modifier genes.  One interesting finding was that in the identified families, the parents who were affected by polycystic kidney disease did not have CHF.

Although this study demonstrates that CHF and portal hypertension can occur with AD-PKD, CHF and portal hypertension are a characteristic finding with AR-PKD.  With AD-PKD, the liver cysts originate from biliary microhamartomas (von Meyenburg complexes) and are not in continuity with the biliary tree.  In contrast, patients with AR-PKD have cystic dilatations of the biliary system; this combination is called Caroli syndrome.  Due to these differences, unlike AR-PKD, AD-PKD does not typically result in portal hypertension.

Additional references on congenital hepatic fibrosis:

  • -Hepatology 2010; 52: 2223. Review. Medical/Surgical & Tx options.
  • -Am J Med Genet C Semin Med Genet 2009; 151C: 296-406.  Liver disease and kidney disease in ciliopathies.
  • -NEJM 2008; 359: 1477.  Review of autosomal dominant polycystic kidney disease.  ~80% develop liver cysts.
  • -NEJM 2007; 356: 1560. Nice pic of resected liver with polycystic liver disease in 51 year old.
  • -J Pediatr 2006; 149: 159. Review and NIH protocol for enrolling patients. Clinical GI issues: recurrent cholangitis, portal htn, cholelithiasis, and cholangiocarcinoma.
  • -Pediatr Transplantation 2005; 9: 634-9.
  • -Hepatology 2004; 40: 774-82.
  • -Surg Endosc 2005; 19: 130-32.
  • -Gastorenterol Clin N Am; 2003; 32: 857-75. “Heritable disorders of the bile ducts”