Hereditary Hemochromatosis - HH

Today we discussed an approach to a very classic internal medicine problem, a patient presenting with a new diagnosis of cirrhosis.  One of our former CMR's, recently inducted into the CMR hall of fame, Dr. Isaac Bogoch led the morning report!

Team 1 had a discussion about hereditary hemochromatosis (HH) as a potential cause for this presentation, which is a common genetic condition that is treatable if diagnosed early.

Genetic Features:

HH is an autosomal recessive iron-overload disorder associated with mutation of the HFE-gene on chromosome 6.  This results in a substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y).

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The original mutation is thought to be approximately 2000 years old, originating in northwestern Europe.  The defect is thought to provide women of child bearing age with some protection related to iron deficiency, and so propagated across northern Europe following the path of the Vikings.

The end result of this mutation in the HFE gene is high levels of iron being absorbed from the GI lumen, and dysregulation of iron storage and metabolism by both the liver and macrophages.  High levels of iron are released into the bloodstream and can deposit in various tissues leading to organ dysfunction.

The frequency of Heterozygotes amongst the caucasian population in the United States and Western Europe is approximately 10%

Ref: Pietrangelo. NEJM 2004. Hereditary Hemochromatosis.

Organs affected:

The main organs that are affected by iron deposition include the liver (leading to hepatits, and potentially cirrhosis), the heart (leading to cardiomyopathy), the pancreas (bronze diabetes), and various endocrine organs (the pituitary and testes).  HH is truly a multi-system disease.

Clinical Features:

The main clinical features include liver function abnormalities (75%), weakness (74%), skin pigmentation (70%), diabetes mellitus (48%), arthralgias (45%), and erectile dysfunction (45%)

Diagnosis:

A transferrin saturation > 45% is 95% specific for HH, and a serum ferritin level > 250 mcg/L is 85% specific in men, and 97% specific in women.  MRI or liver biopsy can also be helpful in making a diagnosis of iron overload states.

Ultimately, we have genetic testing for the HFE gene and other more uncommon genes (H63D) that can cause HH.

Women may have lower than normal ferritin levels because of menstruation, and so often the diagnosis of HH in women is not identified until after menopause.

Management:

The main treatment for HH is the ancient art of phlebotomy.  The target for phlebotomy is a ferritin usually less than 50.  It may take weekly phlebotomy (>500 mL of blood per week) in order to achieve this target.  Each 500 mL of blood contains approximately 250 mg of iron.  A patient with HH may have up to 10 grams (10 000 mg) of excess iron stores, so it may take many phlebotomies (1 per week, for a year) in order to achieve the target end point (ferritin <50 p="">
References:
Hereditary Hemochromatosis - A New Look at an Old Disease. Pietrangelo, A. 2004. New England Journal of Medicine.

UptoDate.

Lemierre Syndrome

A special thank you to Dr. Paul Bunce who did an amazing job and received an unprecedented ovation with morning report today.  Also, thank you to Team 1, Dr. Lindsay Melvin and Dr. Anthony Lott who presented a fascinating case!

Today we discussed a case of sepsis secondary to an acute oropharyngeal infection cause by the organism Fusobacterium necrophorum.

This prompted a discussion of the main syndrome associated with Fusobacterium necrophorum,   Lemierre Syndrome.

Some key learning points:

1.) Pharyngitis (sore throat) is the key presenting symptom - (80 - 87%) of cases
2.) There can be metastatic lesions (septic emboli) in the lung - 80% of cases
3.) Metronidazole or Clindamycin are the key antibiotics to cover Fusobacterium necrophorum
4.) Anticoagulation is controversial and is not the standard of care currently, but a consultation with hematology may be warranted.
5.) Early surgical intervention may be needed if the patient does not respond or improve with initial therapy.

Lemierre Syndrome:
The other name given to this condition is postanginal septicemia, which involves septic thrombophlebitis of the internal jugular vein, secondary to an acute oropharyngeal infection.  The syndrome was first characterized by Andre Lemierre (1875-1956) in 1936, who reported on dozens of cases from his own clinical experience.  He was a physician, and professor of microbiology and infectious diseases.  He published a description of 20 cases in The Lancet describing the clinical syndrome.

The key clinical features of this syndrome are that the initial source is usually within the pharynx (87% of cases), and IJV thrombus is present in approximately 70% of cases.  It can also cause metastatic lesions in the lung (80%) and joints (16% of cases).

The key symptoms and signs are sore throat (80%), fever (80%), and swollen or tender neck (52%).  Most of the diagnosis are made via cultures (70%), or radiology (IJ thrombus) - 15%.

The main laboratory findings are leukocytosis (75%) and thrombocytopenia (24%), and hyper bilirubinemia (32% of cases).

From: The Evolution of Lemierre Syndrome. Chirinos, et. al. Medicine. 2002

Most cases of Lemierre syndrome occur in younger patients (usually 16- 25 years of age).

The usual infectious agent in Lemierre syndrome is Fusobacterium necrophorum (82% of cases).  Other bacteria that can cause this syndrome include Bacteroides sp., and Group B and C Streptoccus.

This bacteria is a normal inhabitant of the oral cavity, and is a strict anaerobe, non-motile gram negative rod.  It has a characteristic appearance on gram stain (filaments, short rods, and coccoid elements).

Management:

Supportive Care:
A concern in any patient presenting with an oropharyngeal abscess is potential airway compromise, so stridor or any signs of respiratory distress should prompt a clinician to notify the ICU.  These patients can also become very sick, and may require ionotropic support.

Antimicrobials:
The initial management to a patient with suspected Lemierre syndrome includes antimicrobials with anaerobic coverage.  Either Metronidazole or Clindamycin are appropriate, with possibly additional coverage in the empiric setting for a polymicrobial infection.

Examples of empiric coverage: 
Cefazolin or Penicillin  G + Flagyl or Clindamycin

Vanco + Flagyl (if MRSA is suspected)

If the patient is septic, the "big guns" (Pip/Tazo, Meropenem) also provide excellent empiric coverage for this syndrome (gram positives, gram negatives, and anaerobic coverage).

Imaging:
Diagnostic Imaging: CT, MRI, or U/S to assess the neck and pharyngeal space, as well as imaging of the vessels is important.  Practically on call overnight a CT scan with contrast would be the imaging modality of choice.

Anticoagulation:   
The role of anticoagulation for an IJ thrombus in a patient with Lemierre syndrome is controversial. The outcome of most patients is very good (mortality is 6.4% in one case series).  There are no RCT's to clarify this question, but a discussion with Infectious Diseases and Hematology should be a part of the initial management plan.

Surgical Debridement / Source Control:  
If the patient has uncontrolled sepsis, or a more complication soft tissue infection (abscess, etc.)  Than a consultation with a surgical specialist is also warranted.

Reference:
The Evolution of Lemierre Syndrome.  Chirinos, J.A. et al. 2002. Medicine. 81: 458-65.

Lemierre Syndrome. Wright, W.F. et al. 2012. Southern Medical Journal. volume 105. Number 5.