Sandbox: HS
Obliterative endophlebitis in the terminal hepatic veins of the human liver lobule was first reported by a pathologist from Prague in 1905, with the only etiologic suggestion being syphilis.1 In 1954, terminal vein lesions were described in Jamaican drinkers of bush tea, characterized by obliteration of hepatic vein radicals by varying amounts of subendothelial swelling and fine reticulated tissue.2 At later stages, a fibrous pericentral scar developed. In the early 1960's, studies of the effects of ionizing radiation on mammalian tissues documented that the hepatic vasculature could be damaged by this mechanism,3 in the absence of antecedent vascular thrombosis.4,5 The most striking example of an obliterative venous lesion induced by irradiation was documented in humans with lung tumors receiving radiation treatment; both the lung vasculature and that of the dome of the liver that was included in the radiation field developed vascular obliteration, but not the remainder of the unexposed liver.6 Shortly thereafter, induction of obliterative venopathy following heavy irradiation directly of the human liver for metastatic disease was reported in 12 patients receiving upper abdominal irradiation by the Stanford Linear Accelerator.7 Thus, by the mid-1960s, the concept of hepatic veno-occlusive disease was well-established, induced by either chemical or radiation toxicity, and as a lesion separate from Budd-Chiari syndrome and Banti syndrome.8,9
In the late 1970's, similar histologic lesions were reported from outbreaks in India and Israel, attributed to contamination of wheat and traditional herbal remedies with plant toxins.10,11 The histological lesions resembled previously described hepatic veno-occlusive lesions described in rats poisoned with Senecio plant extracts12 or Crotolaria.13 This form of liver toxicity was ultimately attributed to hepatic exposure to plant pyrrolizidine alkaloids,14 establishing these plant toxins as the cause of veno-occlusive disease in users of herbal teas.
Bone marrow transplantation for humans with leukemias became a therapeutic option during the 1960s. Initial challenges to this new therapy were preservation of harvested marrow, and achieving successful marrow engraftment.15 Reports of hepatic veno-occlusive disease in patients undergoing bone marrow transplantation emerged in the 1970's,16 followed by numerous reports which established the following apparent risk factors: bone marrow transplantation for malignancy, involving intense chemotherapeutic and radiation conditioning regimens; patient age over 15 years; and in particular, abnormal pretransplant serum levels of liver enzymes.17–19 The presence of metastatic liver disease in patients undergoing bone marrow transplantation for solid tumors and lymphomas also predisposed to veno-occlusive disease.20,21 In these initial years after recognition of veno-occlusive disease as a complication of induction regimes prior to bone marrow transplantation, the incidence of veno-occlusive disease varied from 21% to 25% in allogeneic graft recipients,19,21,22 to 5% in recipients of autologous marrow.20,23,24 In the four decades since routine use of bone marrow transplantation for solid malignancies, lymphomas and leukemias, induction regimes and therapies have helped improve, but not eliminate, the incidence of this condition in the transplant population. Its incidence now is primarily in the setting of hematopoietic stem cell transplantation, but SOS may occur in other settings as well
A central pathogenic event is toxic destruction of hepatic sinusoidal endothelial cells (SEC), with sloughing and downstream occlusion of terminal hepatic venules.
Sinusoidal obstruction syndrome (SOS) occurs due to obstruction of the hepatic venules and sinusoids rather than hepatic vein or inferior vena cava as seen in Budd Chiari syndrome. Hepatic sinusoidal obstruction syndrome (SOS) is mainly seen in hematopoietic cell transplantation. The development of sinusoidal obstruction syndrome (SOS) begins with the injury to the hepatic venous endothelium. It is thought that preexisting liver disease increases the risk of developing sinusoidal obstruction syndrome (SOS) due to impairment of drug metabolism which predisposes to the endothelial injury. The endothelial cells in patients with hepatitis may have abnormal expression of adhesion molecules and procoagulant factors. The deposition of fibrinogen and factor VIII within the sinusoids leads to their dilation and congestion by erythrocytes. The progressive occlusion of venules leads to widespread zonal liver disruption and centrilobular hemorrhagic necrosis. The later changes in sinusoids include deposition of collagen, sclerosis of venular walls, fibrosis of the lumens and ultimately occlusion of hepatic venules. The severity of symptoms depends on the number of sinusoids involve and severity of the histologic changes.
Organ System | Specific Issues | Management Recommendations |
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Central Nervous System | Cerebral edema and intracranial hypertension | a) Intracranial pressure monitoring: (III)
b) Prophylactic hypertonic saline: (I):❑ Hypertonic saline i.v bolus (20 ml of 30% sodium chloride or 200 ml of 3% sodium chloride)[4] for prophylactic induction of hypernatremia in patients with
c) Intracranial hypertension treatment:
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Grade I/II encephalopathy | ❑ Frequent neurological assessment with avoidance of stimulation and sedation ❑ Small doses of short-acting benzodiazepines in case of unmanageable agitation ❑ Stat brain CT to rule out other causes of altered mental status ❑ Consideration for transfer to a liver transplant facility and listing for transplantation at the earliest ❑ Lactulose (possibly helpful and may interfere with surgical field by increasing bowel distention during liver transplantation) (III) ❑ Infection surveillance ❑ Antibiotic prophylaxis against infections (possibly helpful) ❑ Infection treatment as required | |
Grade III/IV encephalopathy | Besides managing the patient similar to grade I/II encephalopathy
| |
Cardiovascular System | Hemodynamic abnormalities | ❑ Fluid resuscitation and maintenance of adequate intravascular volume (initiate hypotension treatment with intravenous normal saline) (III) ❑ Systemic vasopressor support (dopamine, epinephrine, norepinephrine) as needed (II-1) ❑ Vasopressinorterlipressin added to norepinephrine in norepinephrine-refractory cases (used cautiously in severely encephalopathic patients with intracranial hypertension) (II-1) ❑ Ensure appropriate volume status with a volume challenge (pulmonary artery catheterization is rarely necessary since it is associated with significant morbidity) (III) ❑ Echocardiography for low cardiac output and right ventricular failure ❑ Goals of circulatory support: (II)
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Respiratory System | Aspiration pneumonitis | ❑ Neurologic observation to monitor level of consciousness ❑ Early endotracheal intubation for depressed level of consciousness |
Hepatic System | Hepatic dysfunction | ❑ NAC administration (acetaminophen as well as non-acetaminophen ALF) |
Metabolic and Renal System | Metabolic abnormalities and renal failure | ❑ Frequent monitoring and correction of derangements in glucose, potassium, magnesium and phosphate (III) ❑ Continuous modes of hemodialysis (if needed) (I) |
Hematologic System | Coagulopathy | ❑ Replacement therapy for thrombocytopenia and/or prolonged prothrombin time with platelet and FFP transfusion respectively in the setting of active bleeding or before invasive procedure (III) ❑ Vitamin K (5-10 mg subcutaneously) (at least one dose)[10] ❑ Plasmapheresis or recombinant activated factor VII (rFVIIa) in case of inadequate correction of severely elevated INR and risks of volume overload ❑ Maintenance of adequate platelet count
❑ Prophylaxis for stress ulceration: (I)
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Immunologic System | Infection | ❑ Periodic surveillance for prompt initiation of antimicrobial treatment of infections at the earliest sign of active infection or deterioration (progression to high grade hepatic encephalopathy or elements of the SIRS) (III) ❑ Antibiotic prophylaxis (possibly helpful in patients with coagulopathy, organ failure, encephalopathy and in whom illness progression is considered likely - not proven) (III) |
Etiology | Diagnostic Indicators | Management Recommendations |
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Acetaminophen toxicity | ❑ H/o of acetaminophen intake (toxic dose >10 gm/day or >150 mg/kg) ❑ Acetaminophen in blood and/or urine ❑ Aminotransferase levels >3500 IU/L with low bilirubin levels, in the absence of apparent hypotension or cardiovascular collapse (suspected acetaminophen toxicity in the absence of a positive history because acetaminophen is the leading cause of ALF at least in the United States and Europe)[12] |
❑Activated charcoal: 1g/kg PO within 1 hour after drug ingestion (may be beneficial even when administered within 3-4 hours after ingestion)[13] and prior to starting NAC (I) ❑ Nomogram (helps determining the likelihood of serious liver damage but does not exclude possible toxicity) ❑ NAC: 140 mg/kg PO or through NGT (diluted to 5% solution), then 70 mg/kg PO q4h x 17 doses or IV loading dose of 150 mg/kg in 5% dextrose over 15 minutes, then maintenance dose of 50 mg/kg IV over the next 4 hours and then 100 mg/kg IV over the following 16 hours *Promptly begin NAC (beneficial even when administered <48 hours after drug ingestion) in all patients with impending or evolving liver injury due to acetaminophen (II-1) *NAC may be used in cases of ALF due to suspected acetaminophen poisoning (III) *NAC is recommended even in case of non-acetaminophen ALF[14] |
Acute fatty liver of pregnancy/HELLP | ❑ Jaundice and hypertension ❑ Coagulopathy ❑ Thrombocytopenia ❑ Proteinuria ❑ Hypoglycemia ❑ Steatosis in liver imaging or biopsy |
❑ Early diagnosis and prompt delivery (III) ❑ Adequate supportive care ❑ Consider transplantation for postpartum deterioration (III) |
Acute ischemic injury | ❑ H/o cardiac arrest ❑ Any period of significant hypovolemia/hypotension, or severe CHF (hypotension is not documented always) ❑ Any associated renal dysfunction & muscle necrosis ❑ Elevated aminotransferase levels responding to fluid resuscitation |
❑ Adequate cardiovascular support (III) |
Autoimmune | ❑ Positive serum autoantibodies (may be absent) ❑ Positive liver biopsy (confirms diagnosis when autoimmune hepatitis is suspected and autoantibodies are negative) (III) |
❑ Prednisolone (start with 40-60 mg/day, especially in the presence of coagulopathy and mild hepatic encephalopathy) (III) ❑ Consider transplantation and do not delay while awaiting response to steroid treatment (III) |
Budd-Chiari | ❑ Abdominal pain ❑ Ascites ❑ Hepatomegaly ❑ Blood tests positive for hypercoagulability ❑ Positive findings during liver imaging (CT, doppler USG, venography or magnetic resonance venography) (confirms diagnosis) |
❑ Liver transplantation (provided underlying malignancy is excluded) (II-3) |
Drug induced | ❑ H/o hepatotoxic drug intake (usually idiosyncratic hepatotoxic drug intake within first 6 months after drug initiation; continuous usage of potentially hepatotoxic drug for more than 1 to 2 years is unlikely to cause de novo liver damage) ❑ H/o inclusive of details (including onset of ingestion, amount and timing of last dose) concerning all prescription and non-prescription drugs, herbs and dietary supplements taken over the past year (III) ❑ Determine ingredients of non-prescription medications whenever possible (III) |
❑ Discontinue all but essential medications in the setting of possible drug hepatotoxicity (III) ❑ NAC (may be beneficial for ALF induced by drugs) (I) |
Malignant infiltration | ❑ Massive hepatomegaly ❑ Malignant infiltration in liver imaging or liver biopsy (confirms or excludes diagnosis) (III) |
❑ Appropriate management of underlying malignancy ❑ Supportive care |
Mushroom poisoning | ❑ H/o recent mushroom intake ❑ Severe GI symptoms like nausea, vomiting and diarrhea within hours or a day of ingestion (suspected mushroom poisoning in the absence of a positive history) |
❑ Early gastric lavage and activated charcoal administration ❑ Penicillin G 300,000-1 million units/kg/day or Silibinin 30-40 mg/kg/day IV or PO, 3-4 days (silymarin in Europe and south America; milk thistle in north America)[15] ❑ NAC (III) ❑ Liver transplantation (the only lifesaving option) (III) ❑ Fluid resuscitation (as needed) |
Viral | ❑ Toxically appearing patients with skin lesions (HSV) ❑ Positive hepatitis virus serology ❑ HSV positive liver biopsy |
❑ Supportive treatment (no virus specific treatment proven to be effective) (III) ❑ Nucleoside and nucleotide analogues (for HBV associated ALF) (III) ❑ Acyclovir (5-10 mg/kg every 8 hours for at least 7 days for HSV or VZV) (III) |
Wilson's disease | ❑ KF ring ❑ Serum bilirubin >20 mg/dL, ❑ Bilirubin:alkaline phosphatase >2.0 ❑ Low serum ceruloplasmin ❑ Elevated serum & urine copper ❑ High copper levels in liver biopsy (III) |
❑ Liver transplantation (III) ❑ Dialysis or hemofiltration or plasmapheresis or plasma exchange |
Intermediate etiology | ❑ Etiology undetermined after all evaluation | ❑ Review drug and toxin intake H/o ❑ Transjugular biopsy (for further evaluation of possible mailgnancy, Wilson disease, autoimmune hepatitis and viral hepatitis) (III) |