Fulminant hepatic failure

Defined as rapid onset of encephalopathy and marked decrease in liver synthetic function within 28d of symptom onset in patient without chronic liver disease

Major etiologies are 1)acetaminophen OD, 2) idiosyncratic drug reaction, 3) Hep B, 4) Hep A, 5) others

Coagulopathy usually precedes encephalopathy, which may quickly progress to coma

It is important to determine the etiology, since specific causes may have specific treatments:
NAC for acetaminophen, penicillin for amanita mushroom poisoning, delivery for acute fatty liver of pregnancy, zinc/trientine for Wilson's.

Pts should be admitted to ICU and transferred to a transplant centre.

Supportive care includes:
glucose (may need d10 drip)
electrolyte replacement
fluids
reversal of coagulopathy
neurochecks >q6h

FFP (4u) may normalize coags for 6h (for procedure or bleeding)

Empiric abx for any sign of infection

Poor prognostic indicators predicting need for transplant:
pH below 7.3 after resuscitation
PTT over 100
Cr over 290
Gr 3 or 4 encephalopathy
Lactate over 3.3 4h post admission


Major causes of transaminases in the thousands:

1) Ischemia
-inflow (hypotension- shock liver, PV thrombosis)
-outflow (CHF, Budd-Chiari)

2) Viral
HAV, HBV (rarely HCV)
Others- EBV, HSV, CMV

3) Drugs/toxins

4) Autoimmune

5) Obstruction/stone

6) Acetaminophen and EtOH both (but rarely EtOH alone)

Link:
Click here for a NEJM case of fulminant hepatic failure from HSV infection that discusses management considerations
Click here for a paper on approach to increased liver enzymes

Celiac disease

Today we discussed malabsorption, and one of its causes, celiac disease. A few key points:

Clinical features of malabsorption:
Chronic diarrhea (esp. steatorrhea)
Weight loss despite adequate intake
Deficiency of fat-soluble vitamins: (ADEK); vit D deficiency may lead to hypocalcemia, vit K deficiency may lead to high INR
Hypocalcemia
B12 and folate deficiency
Iron deficiency
Hypoalbuminemia

Celiac disease is an autoimmune disease involving the small bowel, precipitated by intake of gluten. This autoimmune reaction leads to chronic small bowel inflammation.

Long term complications include small bowel adenocarcinoma and small bowel T-cell lymphoma

Celiac was traditionally thought of as a malabsorption syndrome of children, but it is increasingly recognized in adults, even the elderly. A common way patients come to clinical attention is iron deficiency anemia that does not respond to oral iron supplementation (because the etiology is malobsorption).

Diagnosis:

Gold standard for diagnosis is small bowel biopsy showing villous atrophy.

Serologic tests are also available that have different performance characteristics:
Endomesial IgA antibodies are near 100% specific (remember to check IgA levels, as many patients with celiac disease have low IgA levels)
Tissue transglutaminase antibodies have sensitivity of over 90%, and this is the screening test
Gliadin antibodes are less sensitive and specific (~80% Sn and Sp)

Therapy:
Gluten-free diet
Treat nutritional deficiencies
Celiac disease is associated with hyposplenism; patients should receive the pneumococcal vaccine
Bone loss is common; patients should have a DEXA scan and treatment as appropriate

Monitoring:
Symptoms should improve with gluten-free diet
Serology can be used to monitor response; antibody titers correspond to degree of inflammation.
Non-response should raise suspicion of small bowel lymphoma or non-adherence to gluten-free diet

Link:

Click here for a NEJM review on celiac disease

Acetaminophen toxicity

Today we discussed acetaminophen toxicity. Some key points:

Stages of toxicity:
1) preclinical toxic effect with normal ALT (may see no elevation for first 24h)
2) hepatic injury (elevated ALT)
3) hepatic failure (injury with hepatic encephalopathy)- pts presenting here have 20-40% mortality

Glutathione is necessary for the pathway to a non-toxic metabolite. When it is depleted, NAPQI (the toxic metabolite) is formed.

Overdoses (acute or chronic) deplete glutathione and allow liver injury. N-acetylcysteine (NAC) restores glutathione.

If within 2h of ingestion, activated charcoal is used. Beyond 2h, benefit is limited. With a known time of ingestion, the Rumack-Matthew nomogram is used; if level is above line for time of ingestion, there is risk of hepatic injury and NAC should be given.

When no time is known, usual practice is to treat anyone who may have overdosed and has measurable level.

The nomogram is not useful with chronic ingestion, unknown time of ingestion, and with long-acting preparations

There is a PO NAC protocol (72h) and an IV NAC protocol (20h). There are no head to head trials comparing.

Most toxicologists recommend checking acetaminophen level and ALT prior to stopping NAC. Criteria for stopping NAC are falling ALT and undetectable acetaminophen level.

High risk features (i.e. predictive of fulminant failure): encephalopathy, INR over 6.5, Cr over 300, pH below 7.3, hypoglycemia, hyperbilirubinemia. Note that AST/ALT levels are not predictive of poor outcome; only indicate injury.

Link:

Click here for a NEJM review of acetaminophen toxicity

Stroke in the young patient

Today we discussed stroke in a young patient. Most references use under 45 as the cutoff for invoking some of the possibilities discussed below.

Differential diagnosis to consider for any patient presenting with "stroke", particularly a young patient:

Structural disease (tumor, bleed), seizure (Todd's paresis), dissection, migraine (esp. migraine sensory aura), demyelination, hypoglycemia. Anything that can cause delirium can cause focal findings when superimposed on a structurally abnormal brain.

In pts 45 and younger, common causes of ischemic stroke include

-Cardioembolic is #1 etiology (structural heart disease, endocarditis, others)

-Always consider dissection, even in the absence of trauma (esp if pain with onset). Dissections are usually extracranial, assoc with trauma or neck manipulation.

-Vasculitis

-Hypercoagulable state

-Cocaine, amphetamines

-Sickle cell disease

-Migranous stroke

More exotic causes: CADASIL, MELAS, Moya-moya

In many patients, an underlying cause is never found.

Workup:

CT/MRI/MRA/MRV

TEE

carotid doppler

thrombophilia screen

skin bx if suspect CADASIL

Antiphospholipid antibodies

Link:
Click here for NEJM review of PFO and stroke in young patients

NMS and serotonin syndrome

Today we discussed neuroleptic malignant syndrome and serotonin syndrome. A few points:

Neuroleptic malignant syndrome:
Syndrome of altered mental status, fever (often over 40), marked rigidity, CK elevation (usually over 1000), and autonomic instability (including hypertension, arrhythmias, tachycardia).

Seen in the context of

1) New or altered dose of antipsychotic medication (usually "typicals")
2) Withdrawal of dopaminergic medications (e.g. antiparkinsonians)
Treatment is discontinuation of drug (or restarting if withdrawal), possibly dantrolene or bromocriptine)

There is an extensive differential diagnosis of components of this presentation, the most important of which to exclude are CNS infections (meningitis, encephalitis), other systemic infections, seizures, intoxications, withdrawal states.

Serotonin syndrome

Related, but distinct disorder that results from overstimulation of serotonin receptors.

It occurs in the setting of substances that either increase serotonin release (e.g. ecstasy, cocaine, amphetamines), or inhibit serotonin reuptake (SSRIs, SNRIs, tricyclics, MAOIs)

Presentation can include mental status change, diarrhea, flushing, diaphoresis, tremor, restlessness.
Physical exam may show fever, hyperreflexia, myoclonus, rigidity, autonomic instability.

Tx: Stop serotonergic substance. If severe, aggressive cooling, benzos, cyproheptadine (antihistamine with antiserotonin effect)

NMS vs. serotonin syndrome differences
Serotonin syndrome may have shivering, hyperreflexia, myoclonus, flushing (all uncommon in NMS)

NMS tends to have more prominent CK elevation, rigidity and higher temperatures

Poison control consultation is an important component of managing both of these situations.

Links

Click here for a CMAJ review of NMS

Click here for a CMAJ review of serotonin syndrome

Acute visual loss

Today we discussed the concerning symptom of acute visual loss. Some points:

Monocular visual loss:

1) TIA (i.e. amaurosis fugax; curtain-like classically) - if not transient, represents branch or central retinal artery occlusion. These pts are at high risk for stroke. May see cherry red fovea and Hollenhorst plaques (cholesterol)

2) Central retinal vein (or branch) occlusion- can be transient or permanent, sometimes associated with hypercoagulability. May see engorged veins, hemorrhage.

3) Anterior Ischemic Optic Neuropathy (AION).
This is divided into "arteritic" and "non-arteritic".
Arteritic essentially means temporal arteritis.
Non-arteritic means no specific cause; HTN and DM2 are risk factors

4) Optic neuritis- demyelination, compression (abscess, tumor), hereditary causes

5) Primary ophthalmologic causes: Retinal detachment, vitreous hemorrhage or detachment, closed angle glaucoma, maculopathy,

Acute binocular blindness suggests a toxic cause (e.g. methanol, carbon monoxide, ethabutol, others). Stroke (cortical blindness from visual cortex involvement) and migraine are also on the differential.

Link:
Click here for a BMJ website outlining approach to visual loss