HepatoBiliary Dysfunction in Home TPN Patients

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Hepato-Biliary Dysfunction in Home TPN Patients

• Working Group Meeting
• April 24-26, 2003, Vancouver, BC
• Dr. Leah Gramlich, Dr. Tara Chalmers-Nixon
• University of Alberta

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Objectives

• Prevalence of hepatobiliary complications
• Clinical features
• Etiology of TPN hepatobiliary complications
• Diagnostic work-up
• Optimizing the TPN prescription
• Therapeutic options

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Case presentation

• 53 F with ileo-colonic Crohns disease x 22yrs
• Developed ischemic small bowel 2 mechanical
  bowel obstruction from adhesions
• 6 feet of small bowel, 1-2 feet of colon remain
• Persistent severe diarrhea with oral intake
• Meds Codeine 60mg qid, multivitaminADEK daily,
  Pantoloc bid, Clomipramine 25 mg daily, Mg
  rougier, T3 prn

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Case contd

• Height 165 cm
• Weight 42.5 kg
• Started on TPN March 29, 2001
• By September, 2001, weight 56.8 kg
• September, 2002 elevated liver enzymes

BMI 15.6 IBW 54-68 kg
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Case contd

• TPN prescription, November 2002
• Weight 49.5 kg
• Infusion 6/7 days
• 1289 kcal (26 kcal/kg)
• 69g protein, 180g Dextrose, 40g lipid
• 200mg carnitine
• Initiated work-up of abnormal liver tests

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Case contd

• Diagnostic Work-up
• Monthly LFTs
• Liver U/S
• Hepatitis work-up HCV, HBV, HAV, quantitative
  Igs, AMA, ASMA, alpha 1 A-T, Cu, Ceruloplasmin,
  Fe, TIBC
• Hemachromatosis genetics if indicated
• MRCP/ERCP
• Liver biopsy
• Hepatologist referral

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Case contd

• Therapy algorithm (simultaneous)
• Minimize CHO in TPN
• Enhance po intake/enteral nutrition
• Ursodeoxycholic acid
• Cyclic antibiotics
• Evaluation for intestinal transplantation

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Oct/Nov, 2002
Lytes - normal Conjugated bili - 116 Ferritin -
461 Fe - 7 TIBC - 49 Satn - 0.14 Quant. IgGs -
Nml Ceruloplasmin - 0.50 AMA, ASMA negative
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Oct/Nov, 2002
Lytes - normal Conjugated bili - 116 Ferritin -
461 Fe - 7 TIBC - 49 Satn - 0.14 Quant. IgGs -
Nml Ceruloplasmin - 0.50 AMA, ASMA negative
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Case contd

• Abdominal ultrasound, Oct. 9, 2002
• Enlarged homogeneous liver
• Normal gallbladder, spleen, kidneys, pancreas
• MRI/MRCP, Dec., 2002
• No obvious biliary ductal abnormallity noted

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Case contd

• Liver biopsy, November 15, 2002
• Severe cholestasis and balloon degeneration of
  hepatocytes
• Acidophil bodies, hypertrophied Kupffer cells
  with PAS pigment
• Triadal fibrosis, biliary ductular proliferation
  with inflammatory infiltrate
• Dx hyperalimentation (TPN) cholestasis

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Histology
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Case contd

• Started on URSO 750 tid and Cipro 500 bid x 2
  weeks, November 21, 2002
• Follow-up labs

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Case contd

• Hepatology referral Dec. 11, 2002
• Concurred with diagnosis of TPN cholestasis
• Agreed that changes to TPN, URSO and Abx had a
  beneficial effect on liver enzyme tests

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Objectives

• Prevalence of hepatobiliary complications
• Clinical features
• Etiology of TPN hepatobiliary complications
• Diagnostic work-up
• Optimizing the TPN prescription
• Therapeutic options

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TPN and Liver Complications

• Abnormal liver function tests 25-100
• Liver Failure15-40
• Cavicchi et al (ann int med. 2000132525-32)
• Seidner et al ASPEN03

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TPN and Liver Complications

• 65 patients develop cholestasis after a mean of
  6 months
• Prevalence of complicated TPN associated liver
  disease - 26/-9 at 2 yrs - 50/-13
  at 6 yrs - 22 of all deaths attributable to
  TPN liver disease

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Biochemical Markers of Liver Disease
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Time Course of Changes in Liver Tests after
Initiating TPN
JPEN 1554. 1991
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Biochemical Markers of Liver Disease In HTPN

• Cavicchi Cholestasis ggt, bili, Alk phos gt1.5
  x uln (require 2/3)
• Seidner mild lt 2x uln moderate 2-5x
  uln severe gt5x uln Liver
  failure bili gt3mg/dl, alblt3.2 g/dl, PT gt 3
  seconds prolonged

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TPN Liver Disease Histology
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Clinical Syndromes

• NAFLD NASH-type, steatosis, phospholipidosis,
  steatohepatitis
• Fibrosis
• Micronodular Cirrhosis
• Cholestasis
• Cholelithiasis, Choledocholithiasis
• Acalculous cholecystitis

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Risk Factors for TPN-Related Liver Disease

• Patient factors age, low birth weight,
  preexisting liver disease, microsepsis
• GIT factors bowel remnant lt50cm
• Nutritional Factors
• limited oral or enteral intake
• increased reliance on TPN
• increased duration of TPN
• composition of TPN lipid, CHO, Pro, other

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Etiology of TPN Hepatobiliary Disease

• Factors not related to TPN
• Factors related to TPN

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Etiology of TPN Hepatobiliary Disease
A Inadequate bile fomation B Nutritional
deficiency C Inadequate stimulation
of Enterohepatic bile circulation And intestinal
function
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Etiology of TPN Hepatobiliary Disease

• Inadequate stimulation of the enterohepatic
  circulation
• lack/reduction of CCK secretion
• lack/reduction of gallbladder contraction and
  emptying
• reduction of bile flow and stimulation at level
  of hepatocyte
• immaturity of biliary secretory system in
  neonates

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Etiology of TPN Hepatobiliary Disease

• Abnormal bile acid metabolism
• bacterial overgrowth in absence of of enteral
  stimulation and presence of enteral stasis
• promote formation of lithocholate from
  chenodeoxycholate
• deconjugation of taurine and glycine from bile
  acids

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Etiology of TPN Hepatobiliary Disease

• Sepsis and Inflammation formation of cholestatic
  endotoxins
• bacterial overgrowth in patients with altered GIT
  motility
• ?bacterial translocation
• CVL related sepsis
• Other septic foci
• SBS Chronic inflammation Cholestasis

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Evidence for Inflammation in TPN Cholestasis

• Increased levels of TNF in HTPN pateints (Reimund
  J et al. Nutrition 17(4)300-304)
• Hepatic cholestasis associated with reduction in
  serum albumin (Burstyne, Jensen. Nutrition
  200016(11/12)1090)
• Subgroup of HTPN pateints without inflammation,
  no cholestasis (McCowan, Ann int med 2000.
  133(12)1009-10)

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Etiology of TPN Hepatobiliary Disease Related to
TPN

• Lipid - deficiency/excess/type
• Carbohydrate/calories
• Protein - deficiency/excess
• Micronutrients

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TPN Toxicity Lipid

• Mechanisms
• high in n-6 fatty acids, low/absent n-3 fatty
  acids stimulate macrophage activiation
• phospholipidosis and microvacuolar steatosis with
  lipid emulsions (20 with 1/2 that in 10)
• impaired response to endotoxin
• impaired phagocye function
• ?plant phytosterols

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TPN Toxicity Calories and Carbohydrate

• Mechanism altered insulinglucagon ratio in
  portal circulation leads to hyperinsulinemia and
  conversion of glucose to fat in liver
• Limit infusion rate to lt 4mg/kg/min

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TPN Toxicity Protein

• ?Mechanisms
• Altered cannalicular bile flow, permeability
• depletion of ATP with excess methionine
• May be related to deficiency or excess (MET, CYS
  (Taurine), TRY byproducts)

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TPN Toxicity Other

• Manganese toxicity
• Taurine deficiency
• conditionally essential in premature infants
• role in conjugating bile acids
• Carnitine Deficiency synthesized from LYS and
  MET in liver and kidney
• conditionally essential in neonates
• role in LCFA transport

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Sepsis as a Cause of Cholestasis

• Source CVL, GIT, billiary stasis
• Findings - sepsis ass. with increased LFTs
• reduction of LFTs after sepsis Rx
• Mechanism
• ?toxic effect of endotoxin or LPS on
  hepatobilliary system
• ?altered hepatic secretion
• ?TNF secretion
• ? Increase GIT permeability

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Investigation of Abnormal LFTs in Home TPN
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Therapeutic Options

• Nutrition related
• Avoid overfeeding of macro and micronutrients
  to avoid liver overload with nutrients
• Enterally feed to preserve intestinal
  integrity, hormonal balance, enzyme secretion,
  and prevent bacterial translocation
• Cycle PN to avoid continuous liver overload

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Therapeutic Options

• Not nutrition related
• Avoid/treat sepsis to avoid bacterial and
  endotoxin hepatototoxic effects
• URSO to increase bile flow, reduce toxic bile
  acids
• CCK to increase gallbladder contractility
• Antibiotics to inhibit bacterial overgrowth
• Cholestyramine treat pruritis, decrease diarrhea
  in SBS

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Optimize the Nutrient Prescription

• Stimulate the GI Tract
• advance PO intake
• Consider EN
• Treat symptoms that limit oral intake

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Nutrient Prescription

• Avoid overfeeding
• 25-35kcal/kg IC if in doubt
• Limit CHO to lt 4mg/kg/min
• Limit fat to lt 1gm/kg if cholestasis develops,
  consider 0.5gm/kg

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Nutrient Prescription

• Provide a mixed fuel substrate (lipid 25-30 of
  calories)
• Cycle TPN
• Replete suspected deficiencies carnitine,
  taurine, choline

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Angelico Della Guardia, APT 2000 14(2)54-7
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Therapeutic options

• Postulated mechanisms
• Immature or altered biliary secretory system
• Translocation of gut bacteria
• Abnormal amino acid uptake
• May cause formation of toxic bile salts known to
  cause cholestasis by damaging bile canaliculi
• Excess lipids

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Therapeutic options

• Postulated mechanisms
• Immature or altered biliary secretory system
• Translocation of gut bacteria
• Abnormal amino acid uptake
• May cause formation of toxic bile salts known to
  cause cholestasis by damaging bile canaliculi
• Excess lipids

Antibiotics
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Therapeutic options - not related to TPN

• Rule out other causes
• UDCA
• Antibiotics
• CCK
• Others (Phenobarbital, Rifampin, anti-TNF)

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UDCA

• Hydrophilic bile acid from liver/intestines
• Stimulates bile formation, reduces cholesterol
  absorption/synthesis, thus decreasing gallstone
  formation
• Administration may increase bile flow, displace
  toxic bile acids, reducing bilirubin levels in
  serum and liver

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UDCA - Animal evidence

• Duerksen et al. Gastro 1996
• Piglet model of TPN cholestasis (n23 total)
• Piglets assigned to three groups I milk fed,
  II TPN fed, III TPNUDCA for three weeks
• TPN fed pigs had markedly reduced bile flow
• Administration of UDCA in TPN fed pigs normalized
  bile flow, and reduced serum and liver bilirubin
  levels

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UDCA - Animal evidence

• Gunsar et al. Hepato-gastro, 2002
• Rabbit model of TPN cholestasis, n18
• Grp A TPN, Grp B TPNUDCA(po), Grp C
  TPNUDCAMNZ
• Grps BC had significantly less elevations in
  liver chemistry Grp C had lower bilirubin levels
  than grp B
• Liver histology Grp A6/6 abnormal, Grp B5/6
  normal, Grp C3/6 normal
• UDCA MNZ improves liver chemistry and histology

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UDCA - Human evidence

• Spagnuolo et al. Gastro, 1996
• 7 children on TPN for intractable diarrhea with
  TPN cholestasis given UDCA po (30mg/kg/d)
• UDCA was associated with decreased liver
  biochemistry and disappearance of stigmata of CLD
• 6/7 children recovered and resumed oral feeding
  eventually

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UDCA - Human evidence

• Beau et al., Journal of Hepatol, 1994
• 9 adults on home TPN for SBS
• UDCA at approx. 12mg/kg/d po for 2 months
• Serum GGT, ALT reduced significantly with UDCA
  treatment
• No significant change in AST, ALP, bili

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Antibiotics

• Proposed to decrease bacterial overgrowth and
  hence endotoxin effects on liver
• There are no controlled trials using antibiotics
  in TPN related hepatobiliary dysfunction
• No consensus as to which antibiotic to use

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Antibiotics - Animal evidence

• Pappo, et al., JPEN, 1992
• Polymyxin B in rat model of TPN related hepatic
  steatosis
• 46 Sabra rats divided into groups
• Grp I (n12) control
• Grp II (n10) TPN
• Grp III (n7) TPN po Polymyxin B
• Grp IV (n17) TPNIV Polymyxin B

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Antibiotics - Animal evidence

• Polymyxin B treated groups had
• less hepatic fat
• less gram negative bacterial counts of the cecum
• significantly less TNF production that TPN fed
  rats w/o antibiotic
• Conluded that Polymyxin B protects by inhibiting
  overgrowth of toxic bacteria, its anti-LPS
  activity thus preventing hepatic steatosis and
  TNF production

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Antibiotics - Human evidence

• Spurr et al., JPEN, 1989
• Retrospective chart review of very low birth
  weight infants empirically treated (or not) with
  oral gent for prevention of NEC depending on the
  institution in which they were born
• N12 in each group
• Grp I po gent 2.5mg/kg q 12h Grp II - none

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Antibiotics - Human evidence

• Significantly reduced incidence of NEC in treated
  group
• Grp I 1/12 developed cholestasis
• Grp II 5/12 developed cholestasis, p0.05
• Concluded that oral gent was protective against
  TPN cholestasis, and warranted a prospective RCT

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CCK

• Hormone that enhances gallbladder contractility
• Proposed to prevent biliary sludge
• Human evidence
• Sitzmann et al. Surgery, Gyne, Obst, 1990
• Placebo controlled RCT of patients on TPN for gt21
  days
• Grp I (n8) IV NS
• Grp II (n7) IV CCK, 50 nanograms/kg IV/day

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CCK

• None of the patients in CCK arm had biliary
  sludge by U/S, 5/8 in control group had sludge
• Better emptying of gb in treatment group

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Intestinal Transplantation

• Survival on home TPN is good
• 98 at 2 yrs
• 80 at 4 yrs
• 65 at 6 yrs
• 56 at 8 yrs
• Survival for intestinal transplantation is about
  50 at 2 yrs
• Not all patients get off TPN entirely (66-69)

Cavicchi et al. 2000 Annals
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Figure 2. Patient and graft survival. The
actuarial patient and death-censored graft
survival vs month after intestinal
transplantation is shown for all 17 patients
undergoing transplantation. (Farmer et al.,
Archives of Surgery 2001)
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Intestinal Transplantation

• Currently reserved for TPN dependent patients who
  develop life-threatening complications such as
• End stage liver disease
• Loss of venous access
• Recurrent sepsis/catheter infections
• Major fluid and electrolyte imbalances
• When life expectancy on TPN falls below 50,
  consider intestinal transplantation

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Phenobarbital

• Proposed to enhance bilirubin conjugation
• Little evidence, and may be harmful
• Not recommended

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Therapeutics summary

• Optimize nutrient prescription
• UDCA beneficial
• Antibiotics probably beneficial
• CCK probably beneficial
• Intestinal transplantation evaluation if survival
  unlikely with ongoing TPN