Neonatal hemochromatosis - Revision history

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Ostermayer: Created page with "Neonatal hemochromatosis (NH) is a clinical syndrome of '''severe neonatal liver disease with extrahepatic iron deposition''' (siderosis).Feldman AG, Whitington PF. Neonatal hemochromatosis. ''J Clin Exp Hepatol''. 2013;3(4):313-320. doi:10.1016/j.jceh.2013.10.004 Nearly all cases are caused by '''gestational alloimmune liver disease (GALD)''', a maternal-fetal alloimmune disorder in which maternal IgG antibodies cross the placenta, attack f..."

2026-03-18T00:51:39Z

Created page with "Neonatal hemochromatosis (NH) is a clinical syndrome of '''severe neonatal liver disease with extrahepatic iron deposition''' (siderosis).<ref name="Feldman2013">Feldman AG, Whitington PF. Neonatal hemochromatosis. ''J Clin Exp Hepatol''. 2013;3(4):313-320. doi:10.1016/j.jceh.2013.10.004</ref> Nearly all cases are caused by '''gestational alloimmune liver disease (GALD)''', a maternal-fetal alloimmune disorder in which maternal IgG antibodies cross the placenta, attack f..."

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Neonatal hemochromatosis (NH) is a clinical syndrome of '''severe neonatal liver disease with extrahepatic iron deposition''' (siderosis).<ref name="Feldman2013">Feldman AG, Whitington PF. Neonatal hemochromatosis. ''J Clin Exp Hepatol''. 2013;3(4):313-320. doi:10.1016/j.jceh.2013.10.004</ref> Nearly all cases are caused by '''gestational alloimmune liver disease (GALD)''', a maternal-fetal alloimmune disorder in which maternal IgG antibodies cross the placenta, attack fetal hepatocytes, and activate complement-mediated destruction.<ref name="Feldman2013"/> NH/GALD is the '''leading treatable cause of neonatal acute liver failure''' and carries '''>90% mortality without treatment'''.<ref name="AASLD">Little Livers, BIG Problems! Gestational Alloimmune Liver Disease. ''AASLD Liver Fellow Network''. 2024.</ref> The emergency physician must recognize the pattern of '''liver failure at birth with massively elevated ferritin and AFP''', initiate '''IVIG empirically''', and arrange '''double-volume exchange transfusion''' and urgent hepatology/neonatology consultation.

==Background==
*'''Not a hereditary hemochromatosis''' — despite the name, NH is an alloimmune disease, not a genetic iron storage disorder<ref name="Feldman2013"/>
*Incidence: approximately 4 per 100,000 live births in the US; extremely rare globally (<1 per 1,000,000)
*GALD accounts for ~95% of NH cases<ref name="Stanford">Neonatal Hemochromatosis. ''Stanford Medicine Children's Health''. 2024.</ref>

===Mechanism===
*Mother becomes sensitized to a fetal hepatocyte surface antigen (the specific antigen remains unidentified)
*Maternal '''IgG antibodies''' cross the placenta (actively transported from ~18 weeks gestation)
*IgG binds fetal hepatocytes → activates '''terminal complement cascade (C5b-9)''' → hepatocyte injury and death<ref name="Feldman2013"/>
*Massive hepatocyte loss → liver failure, congenital cirrhosis
*Secondary '''iron overload''' occurs because:
**Damaged hepatocytes release stored iron
**Impaired hepatic hepcidin production → unregulated iron absorption
**Iron deposits in extrahepatic organs (pancreas, myocardium, thyroid, salivary glands) in a pattern that '''spares the reticuloendothelial system''' (spleen, lymph nodes, bone marrow are not iron-laden — this distinguishes NH from transfusional iron overload)<ref name="Feldman2013"/>

===Recurrence risk===
*'''80-95% recurrence in subsequent pregnancies''' — this is critical information for family counseling<ref name="GALD_recon">Gestational alloimmune liver disease reconsidered. ''World J Gastroenterol''. 2025.</ref>
*Maternal '''IVIG during pregnancy''' (weekly from 18 weeks gestation) reduces recurrence to 5-10% with nearly 100% healthy live births<ref name="Stanford"/>
*First affected pregnancy is ''not'' predictable; typically unrecognized until the affected neonate presents

==Clinical features==
===Presentation at birth or within hours===
*Most NH infants are symptomatic '''at birth or within the first hours of life''' — this distinguishes NH from most other causes of neonatal liver failure, which typically develop over days to weeks<ref name="Feldman2013"/>
*'''Liver failure at birth:'''
**Severe '''conjugated hyperbilirubinemia''' (total bilirubin may exceed 30 mg/dL)
**'''Profound coagulopathy''' (INR often >3; unresponsive to vitamin K)
**'''Hypoalbuminemia'''
**'''Hypoglycemia''' (impaired hepatic gluconeogenesis)
**'''Hyperammonemia'''
*'''Ascites and edema'''
*'''Hepatomegaly''' (liver palpable several cm below costal margin; may also be small if severe cirrhosis)
*'''Oliguria/renal failure''' (hepatorenal syndrome)

===Prenatal findings (may be reported in history)===
*'''Intrauterine growth restriction (IUGR)'''
*'''Oligohydramnios'''
*'''Hydrops fetalis''' (in severe cases)
*'''Stillbirth''' (NH should be considered in unexplained fetal demise)
*Prematurity (about half of NH infants are preterm)<ref name="Frontiers_GALD">Efficacy of IVIG/ET Therapy on GALD. ''Front Pediatr''. 2021;9:680730.</ref>

===Characteristic laboratory pattern===
The following constellation is highly suggestive of NH:
*'''Ferritin: massively elevated''' (typically >800 ng/mL; commonly 2,000-150,000+ ng/mL) — sensitive but not specific, as any severe liver injury elevates ferritin<ref name="Feldman2013"/>
*'''Transferrin: low but hypersaturated''' (saturation often >90-100%) — one of the most characteristic findings<ref name="Medscape_NH">Neonatal Hemochromatosis Workup. ''Medscape''. 2024.</ref>
*'''AFP: very high''' (typically 100,000-600,000 ng/mL — even higher than neonatal baseline)
*'''AST/ALT: disproportionately low''' (often <100 IU/L despite severe liver failure) — this is because there are so few viable hepatocytes remaining that transaminase release is minimal<ref name="Feldman2013"/>
*'''INR markedly elevated''' (often >3)
*Hypoglycemia, hyperammonemia, hypoalbuminemia, metabolic acidosis

==Differential diagnosis==
===Neonatal acute liver failure===
*'''[[Neonatal HSV|Neonatal herpes simplex (HSV)]]''' — the most important alternative diagnosis; '''start empiric acyclovir''' alongside IVIG while differentiating (HSV typically presents slightly later, days 7-14, and has markedly elevated AST/ALT, unlike NH)
*'''[[Tyrosinemia|Tyrosinemia type 1]]''' — very high AFP + coagulopathy (similar to NH); Fanconi syndrome distinguishes; urine succinylacetone is pathognomonic
*'''[[Galactosemia]]''' — after initiation of lactose-containing feeds; reducing substances in urine; ''E. coli'' sepsis
*'''Hemophagocytic lymphohistiocytosis (HLH)''' — fever, hepatosplenomegaly, pancytopenia, hyperferritinemia, hypertriglyceridemia; can closely mimic NH; soluble IL-2 receptor and NK cell activity help distinguish
*'''Hereditary fructose intolerance''' — after fructose/sucrose exposure
*'''Mitochondrial hepatopathy''' (DGUOK mutations, others)
*'''Bile acid synthesis defects'''
*'''Bacterial [[Sepsis|sepsis]]'''

===Key distinguishing features of NH===
*Liver failure '''present at or within hours of birth''' (most other causes present later)
*AST/ALT '''disproportionately low''' for degree of liver failure
*'''Extrahepatic siderosis''' (pancreas, heart, thyroid iron-laden on MRI) with '''splenic sparing'''
*Ferritin and transferrin saturation massively elevated

==Evaluation==
===ED workup===
*'''Hepatic panel:''' AST, ALT (expect disproportionately low), bilirubin (fractionate), albumin
*'''Coagulation studies:''' PT/INR, fibrinogen
*'''Ferritin:''' expect massively elevated (>800 ng/mL; commonly >10,000)
*'''Iron studies:''' serum iron, transferrin, '''transferrin saturation''' (expect >90%)
*'''AFP (alpha-fetoprotein):''' expect markedly elevated
*'''Blood glucose:''' frequent monitoring; anticipate hypoglycemia
*'''Ammonia'''
*'''BMP:''' electrolytes, creatinine (hepatorenal syndrome)
*'''CBC:''' thrombocytopenia (common)
*'''Blood cultures, urinalysis/urine culture''' — to exclude sepsis
*'''HSV PCR''' (blood and CSF if LP feasible) — '''must exclude HSV empirically'''
*'''Lactate'''

===Confirmatory testing for extrahepatic siderosis===
*'''Abdominal MRI (T2-weighted):''' the most useful diagnostic study<ref name="Medscape_NH"/>
**Demonstrates '''low T2 signal in liver and pancreas''' (iron-laden) with '''normal/preserved signal in spleen''' (reticuloendothelial sparing)
**Can also show iron in myocardium and thyroid
**'''Extrahepatic siderosis in pancreas + thyroid is diagnostic''' of NH
**Can be performed within hours of birth
*'''Buccal (minor salivary gland) biopsy:'''<ref name="Feldman2013"/>
**3-mm punch biopsy of lower lip mucosa (must include submucosal salivary glands)
**Prussian blue stain reveals hemosiderin in acinar epithelial cells
**Positive in approximately two-thirds of proven NH cases
**Minimally invasive; can be performed at bedside even with severe coagulopathy (bleeding controlled by local measures; FFP not required beforehand)
*'''Liver biopsy:''' generally '''avoided''' due to severe coagulopathy; if performed, shows hepatocyte loss, giant cell transformation, fibrosis/cirrhosis, hepatocyte siderosis with Kupffer cell sparing; C5b-9 immunostaining supports GALD diagnosis
*If either MRI or buccal biopsy demonstrates extrahepatic siderosis → '''diagnosis of NH is established'''<ref name="Feldman2013"/>

==Management==
===Immediate ED management===
*'''Give one dose of IVIG (1 g/kg IV)''' as soon as NH/GALD is suspected — '''do not wait for MRI or biopsy confirmation'''<ref name="AASLD"/>
**Mechanism: blocks complement-activating antibodies from continuing hepatocyte destruction
**Current expert recommendation: any neonate in liver failure should receive one dose of IVIG while GALD is being evaluated<ref name="Feldman2013"/>
*'''Start empiric IV acyclovir''' (20 mg/kg/dose every 8 hours) simultaneously — HSV disseminated disease is the most important alternative diagnosis and cannot be reliably excluded clinically; treat for both until testing clarifies
*'''Correct coagulopathy:''' FFP, cryoprecipitate (note: coagulopathy in NH is often '''refractory to vitamin K''' because it reflects synthetic failure, not vitamin K deficiency)
*'''Correct hypoglycemia:''' D10W infusion with frequent glucose monitoring
*'''IV fluids:''' cautious volume management (risk of fluid overload with ascites/edema)
*'''Broad-spectrum antibiotics''' if sepsis is in the differential

===Definitive treatment===
*'''Double-volume exchange transfusion (DVET):'''<ref name="GALD_case">Gestational alloimmune liver disease treated with exchange transfusion and IVIG. ''Pediatr Neonatol''. 2022;63(1):94-96.</ref>
**Purpose: physically removes circulating maternal IgG antibodies that are driving hepatocyte destruction
**Performed with '''twice the calculated blood volume'''
**Should be followed immediately by IVIG infusion
*'''IVIG (1 g/kg IV):''' given after DVET to block any remaining antibody-induced complement activation
**May require multiple doses (published cases describe 1-4 doses)
*This combination (DVET + IVIG) has improved survival from ~10-20% (historical) to '''75%''' without liver transplant in the best-reported series<ref name="Feldman2013"/>
*'''Do NOT give mother's breast milk''' — maternal antibodies directed against neonatal hepatocytes may continue to pass through breast milk<ref name="AASLD"/>

===Liver transplant===
*Consider if patient fails to respond to IVIG ± DVET within days
*NH is a common indication for liver transplantation in the first 3 months of life
*INR recovery may take '''4-6 weeks or longer''' after successful immunotherapy — treatment prevents ongoing immune injury but does not reverse damage already sustained<ref name="AASLD"/>

===Therapies of historical interest (largely replaced)===
*'''Antioxidant/chelation cocktail''' (vitamin E, selenium, N-acetylcysteine, prostaglandin E1, deferoxamine) — used before GALD mechanism was discovered; survival only 10-20%; no longer first-line<ref name="Feldman2013"/>

==Disposition==
*'''All suspected NH cases: NICU admission'''
*'''Immediate consultations:'''
**Neonatology (DVET, NICU management)
**Pediatric hepatology/GI (diagnosis confirmation, IVIG, transplant evaluation)
**Pediatric surgery/transplant center (early notification — emergent transplant may be needed)
*'''Transfer to a center with neonatal liver transplant capability''' if not available locally — do not delay IVIG while arranging transfer
*'''Communicate to the family:'''
**90% recurrence risk in future pregnancies
**Prenatal IVIG treatment is available and highly effective for preventing recurrence
**Refer to maternal-fetal medicine for future pregnancy planning

==See Also==
*[[Neonatal hepatitis]]
*[[Neonatal HSV]]
*[[Tyrosinemia]]
*[[Galactosemia]]
*[[Acute liver failure]]
*[[TORCH infections]]
*[[Hemochromatosis]]

==External Links==
*[https://pmc.ncbi.nlm.nih.gov/articles/PMC3940210/ J Clin Exp Hepatol — Neonatal Hemochromatosis (Feldman & Whitington, 2013)]
*[https://www.aasld.org/liver-fellow-network/core-series/clinical-pearls/little-livers-big-problems-gestational-alloimmune AASLD — Little Livers, BIG Problems: Gestational Alloimmune Liver Disease]
*[https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2021.680730/full Front Pediatr — Efficacy of IVIG/ET Therapy on GALD (2021)]
*[https://emedicine.medscape.com/article/929625-workup Medscape — Neonatal Hemochromatosis Workup]
*[https://www.stanfordchildrens.org/en/services/fetal-and-pregnancy-health/conditions/neonatal-hemochromatosis.html Stanford Children's — Neonatal Hemochromatosis]

==References==
<references/>

[[Category:Pediatrics]]
[[Category:GI]]
[[Category:Heme/Onc]]

← Older revision		Revision as of 09:30, 22 March 2026
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	*IgG binds fetal hepatocytes → activates '''terminal complement cascade (C5b-9)''' → hepatocyte injury and death<ref name="Feldman2013"/>		*IgG binds fetal hepatocytes → activates '''terminal complement cascade (C5b-9)''' → hepatocyte injury and death<ref name="Feldman2013"/>
	*Massive hepatocyte loss → liver failure, congenital cirrhosis		*Massive hepatocyte loss → liver failure, congenital cirrhosis
	*Secondary ~~'''~~iron overload~~'''~~ occurs because:		*Secondary iron overload occurs because:
	**Damaged hepatocytes release stored iron		**Damaged hepatocytes release stored iron
	**Impaired hepatic hepcidin production → unregulated iron absorption		**Impaired hepatic hepcidin production → unregulated iron absorption
	**Iron deposits in extrahepatic organs (pancreas, myocardium, thyroid, salivary glands) in a pattern that ~~'''~~spares the reticuloendothelial system~~'''~~ (spleen, lymph nodes, bone marrow are not iron-laden — this distinguishes NH from transfusional iron overload)<ref name="Feldman2013"/>		**Iron deposits in extrahepatic organs (pancreas, myocardium, thyroid, salivary glands) in a pattern that spares the reticuloendothelial system (spleen, lymph nodes, bone marrow are not iron-laden — this distinguishes NH from transfusional iron overload)<ref name="Feldman2013"/>

	===Recurrence risk===		===Recurrence risk===
Line 22:		Line 22:
	==Clinical features==		==Clinical features==
	===Presentation at birth or within hours===		===Presentation at birth or within hours===
	*Most NH infants are symptomatic ~~'''~~at birth or within the first hours of life~~'''~~ — this distinguishes NH from most other causes of neonatal liver failure, which typically develop over days to weeks<ref name="Feldman2013"/>		*Most NH infants are symptomatic at birth or within the first hours of life — this distinguishes NH from most other causes of neonatal liver failure, which typically develop over days to weeks<ref name="Feldman2013"/>
	* Liver failure at birth:		* Liver failure at birth:
	**Severe ~~'''~~conjugated hyperbilirubinemia~~'''~~ (total bilirubin may exceed 30 mg/dL)		**Severe conjugated hyperbilirubinemia (total bilirubin may exceed 30 mg/dL)
	** Profound coagulopathy (INR often >3; unresponsive to vitamin K)		** Profound coagulopathy (INR often >3; unresponsive to vitamin K)
	** Hypoalbuminemia		** Hypoalbuminemia
Line 51:		Line 51:
	==Differential diagnosis==		==Differential diagnosis==
	===Neonatal acute liver failure===		===Neonatal acute liver failure===
	* [[Neonatal HSV\|Neonatal herpes simplex (HSV)]] — the most important alternative diagnosis; ~~'''~~start empiric acyclovir~~'''~~ alongside IVIG while differentiating (HSV typically presents slightly later, days 7-14, and has markedly elevated AST/ALT, unlike NH)		* [[Neonatal HSV\|Neonatal herpes simplex (HSV)]] — the most important alternative diagnosis; start empiric acyclovir alongside IVIG while differentiating (HSV typically presents slightly later, days 7-14, and has markedly elevated AST/ALT, unlike NH)
	* [[Tyrosinemia\|Tyrosinemia type 1]] — very high AFP + coagulopathy (similar to NH); Fanconi syndrome distinguishes; urine succinylacetone is pathognomonic		* [[Tyrosinemia\|Tyrosinemia type 1]] — very high AFP + coagulopathy (similar to NH); Fanconi syndrome distinguishes; urine succinylacetone is pathognomonic
	* [[Galactosemia]] — after initiation of lactose-containing feeds; reducing substances in urine; ''E. coli'' sepsis		* [[Galactosemia]] — after initiation of lactose-containing feeds; reducing substances in urine; ''E. coli'' sepsis
Line 61:		Line 61:

	===Key distinguishing features of NH===		===Key distinguishing features of NH===
	*Liver failure ~~'''~~present at or within hours of birth~~'''~~ (most other causes present later)		*Liver failure present at or within hours of birth (most other causes present later)
	*AST/ALT ~~'''~~disproportionately low~~'''~~ for degree of liver failure		*AST/ALT disproportionately low for degree of liver failure
	* Extrahepatic siderosis (pancreas, heart, thyroid iron-laden on MRI) with ~~'''~~splenic sparing~~'''~~		* Extrahepatic siderosis (pancreas, heart, thyroid iron-laden on MRI) with splenic sparing
	*Ferritin and transferrin saturation massively elevated		*Ferritin and transferrin saturation massively elevated

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	* Coagulation studies: PT/INR, fibrinogen		* Coagulation studies: PT/INR, fibrinogen
	* Ferritin: expect massively elevated (>800 ng/mL; commonly >10,000)		* Ferritin: expect massively elevated (>800 ng/mL; commonly >10,000)
	* Iron studies: serum iron, transferrin, ~~'''~~transferrin saturation~~'''~~ (expect >90%)		* Iron studies: serum iron, transferrin, transferrin saturation (expect >90%)
	* AFP (alpha-fetoprotein): expect markedly elevated		* AFP (alpha-fetoprotein): expect markedly elevated
	* Blood glucose: frequent monitoring; anticipate hypoglycemia		* Blood glucose: frequent monitoring; anticipate hypoglycemia
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	===Confirmatory testing for extrahepatic siderosis===		===Confirmatory testing for extrahepatic siderosis===
	* Abdominal MRI (T2-weighted): the most useful diagnostic study<ref name="Medscape_NH"/>		* Abdominal MRI (T2-weighted): the most useful diagnostic study<ref name="Medscape_NH"/>
	**Demonstrates ~~'''~~low T2 signal in liver and pancreas~~'''~~ (iron-laden) with ~~'''~~normal/preserved signal in spleen~~'''~~ (reticuloendothelial sparing)		**Demonstrates low T2 signal in liver and pancreas (iron-laden) with normal/preserved signal in spleen (reticuloendothelial sparing)
	**Can also show iron in myocardium and thyroid		**Can also show iron in myocardium and thyroid
	** Extrahepatic siderosis in pancreas + thyroid is diagnostic of NH		** Extrahepatic siderosis in pancreas + thyroid is diagnostic of NH
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	**Positive in approximately two-thirds of proven NH cases		**Positive in approximately two-thirds of proven NH cases
	**Minimally invasive; can be performed at bedside even with severe coagulopathy (bleeding controlled by local measures; FFP not required beforehand)		**Minimally invasive; can be performed at bedside even with severe coagulopathy (bleeding controlled by local measures; FFP not required beforehand)
	* Liver biopsy: generally ~~'''~~avoided~~'''~~ due to severe coagulopathy; if performed, shows hepatocyte loss, giant cell transformation, fibrosis/cirrhosis, hepatocyte siderosis with Kupffer cell sparing; C5b-9 immunostaining supports GALD diagnosis		* Liver biopsy: generally avoided due to severe coagulopathy; if performed, shows hepatocyte loss, giant cell transformation, fibrosis/cirrhosis, hepatocyte siderosis with Kupffer cell sparing; C5b-9 immunostaining supports GALD diagnosis
	*If either MRI or buccal biopsy demonstrates extrahepatic siderosis → ~~'''~~diagnosis of NH is established~~'''~~<ref name="Feldman2013"/>		*If either MRI or buccal biopsy demonstrates extrahepatic siderosis → diagnosis of NH is established<ref name="Feldman2013"/>

	==Management==		==Management==
Line 101:		Line 101:
	**Current expert recommendation: any neonate in liver failure should receive one dose of IVIG while GALD is being evaluated<ref name="Feldman2013"/>		**Current expert recommendation: any neonate in liver failure should receive one dose of IVIG while GALD is being evaluated<ref name="Feldman2013"/>
	* Start empiric IV acyclovir (20 mg/kg/dose every 8 hours) simultaneously — HSV disseminated disease is the most important alternative diagnosis and cannot be reliably excluded clinically; treat for both until testing clarifies		* Start empiric IV acyclovir (20 mg/kg/dose every 8 hours) simultaneously — HSV disseminated disease is the most important alternative diagnosis and cannot be reliably excluded clinically; treat for both until testing clarifies
	* Correct coagulopathy: FFP, cryoprecipitate (note: coagulopathy in NH is often ~~'''~~refractory to vitamin K~~'''~~ because it reflects synthetic failure, not vitamin K deficiency)		* Correct coagulopathy: FFP, cryoprecipitate (note: coagulopathy in NH is often refractory to vitamin K because it reflects synthetic failure, not vitamin K deficiency)
	* Correct hypoglycemia: D10W infusion with frequent glucose monitoring		* Correct hypoglycemia: D10W infusion with frequent glucose monitoring
	* IV fluids: cautious volume management (risk of fluid overload with ascites/edema)		* IV fluids: cautious volume management (risk of fluid overload with ascites/edema)
Line 109:		Line 109:
	* Double-volume exchange transfusion (DVET):<ref name="GALD_case">Gestational alloimmune liver disease treated with exchange transfusion and IVIG. ''Pediatr Neonatol''. 2022;63(1):94-96.</ref>		* Double-volume exchange transfusion (DVET):<ref name="GALD_case">Gestational alloimmune liver disease treated with exchange transfusion and IVIG. ''Pediatr Neonatol''. 2022;63(1):94-96.</ref>
	**Purpose: physically removes circulating maternal IgG antibodies that are driving hepatocyte destruction		**Purpose: physically removes circulating maternal IgG antibodies that are driving hepatocyte destruction
	**Performed with ~~'''~~twice the calculated blood volume~~'''~~		**Performed with twice the calculated blood volume
	**Should be followed immediately by IVIG infusion		**Should be followed immediately by IVIG infusion
	* IVIG (1 g/kg IV): given after DVET to block any remaining antibody-induced complement activation		* IVIG (1 g/kg IV): given after DVET to block any remaining antibody-induced complement activation
	**May require multiple doses (published cases describe 1-4 doses)		**May require multiple doses (published cases describe 1-4 doses)
	*This combination (DVET + IVIG) has improved survival from ~10-20% (historical) to ~~'''~~75%~~'''~~ without liver transplant in the best-reported series<ref name="Feldman2013"/>		*This combination (DVET + IVIG) has improved survival from ~10-20% (historical) to 75% without liver transplant in the best-reported series<ref name="Feldman2013"/>
	*'''Do NOT give mother's breast milk''' — maternal antibodies directed against neonatal hepatocytes may continue to pass through breast milk<ref name="AASLD"/>		*'''Do NOT give mother's breast milk''' — maternal antibodies directed against neonatal hepatocytes may continue to pass through breast milk<ref name="AASLD"/>

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	*Consider if patient fails to respond to IVIG ± DVET within days		*Consider if patient fails to respond to IVIG ± DVET within days
	*NH is a common indication for liver transplantation in the first 3 months of life		*NH is a common indication for liver transplantation in the first 3 months of life
	*INR recovery may take ~~'''~~4-6 weeks or longer~~'''~~ after successful immunotherapy — treatment prevents ongoing immune injury but does not reverse damage already sustained<ref name="AASLD"/>		*INR recovery may take 4-6 weeks or longer after successful immunotherapy — treatment prevents ongoing immune injury but does not reverse damage already sustained<ref name="AASLD"/>

	===Therapies of historical interest (largely replaced)===		===Therapies of historical interest (largely replaced)===