Neurosyphilis? Wait… reactive arthritis!

Thanks to Tim for presenting the interesting case of a middle-aged man with h/o inadequately treated syphilis who presented with neck stiffness worse in the mornings, back pain, and blurry vision, admitted for presumed neurosyphilis.  Exam revealed inflammation of T2/T3 joints, L SI joint tenderness, and an inflamed R foot with dactylitis of the 3rd and 4th digits.  Further history revealed a recent gonorrhea/chlamydia for which he was treated and HLA B27 positivity consistent with reactive arthritis!  He was started on NSAIDs with significant improvement of symptoms.


Clinical Pearls:

  • Neurosyphilis is most commonly seen in HIV positive patients and can present at any time after infection.
  • Early neurosyphilis occurs within the first year after infection and involves the CNS, meninges, and vasculature
    • Neurosyphilis presents with posterior uveitis or pan-uveitis whereas reactive arthritis presents with anterior uveitis
  • Late neurosyphilis occurs >10 years after infection and involves the brain and spinal cord parenchyma
  • The four main spondyloarthropathies are ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and IBD-related arthritis.
  • The genital pathogen most commonly associated with reactive arthritis is chlamydia trachomatis.
    • HLA B27 is positive in 30-50% of patients
    • Mainstay of treatment is NSAIDs
    • Disease typically lasts 3-5 months.

 

Syphilis

Clinical manifestations and treatment of different stages of syphilis

Neurosyphilis manifestations

  • Refer to this prior post
  • Early (w/n first year of infection)
    • CSF, meninges, vasculature
    • Symptomatic meningitis
    • Ocular syphilis (posterior uveitis, panuveitis)
    • Meningovascular syphilis
      • Arteritis of any sized vessel which can lead tostroke or spinal cord infarction
  • Late
    • Brain and spinal cord parenchyma
      • General paresis (10-25 years after initialinfection)
        • Progressive dementia
        • Psychiatric symptoms
      • Tabes dorsalis (>20 years after initialinfection)
        • CSF may be completely normal
        • Affects dorsal columns
        • Symptoms
          • Sensory ataxia
          • Argyll-Robertson pupil
          • Lancinating pains
  • Diagnosis
    • Non-treponemal tests (poor sensitivity but highspecificity)
      • VDRL
      • RPR
    • Treponemal tests
      • FTA-ABS
      • Syphilis EIA
    • In an HIV negative patient with suspectedneurosyphilis and a non-reactive CSF-VDRL, one can establish the diagnosis with
      • CSF lymphocytes >5 cells/microL
      • CSF protein concentration >45

Reactive Arthritis

  • Epimiology
    • Young adults, M:F equal
  • Typically follows GI or urogenital infections (several days to weeks after infection)
    • Chlamydia trachomatis (most common genital infection associated)
    • Yersinia
    • Salmonella
    • Shigella
    • Campylobacter
    • E coli
    • C diff
    • Chlamydia pneumoniae
  • Manifestations
    • Mono- or oligoarticular pattern of arthritis,often involving the lower extremities, sometimes associated with dactylitis and enthesitis
    • The triad of arthritis, urethritis, andconjunctivitis is only present in a subset of patients (formerly called Reiter’s syndrome)
    • Ocular manifestions: conjunctivitis, less frequently anterior uveitis, episcleritis, and keratitis.
    • Other: 
      • Skin: keratoderma blennorhagica, erythema nodosum
      • Circinate balanitis 
      • Nail changes resembling psoriatic arthritis
  • Lab
    • E/o of antecedent or concomitant infection
    • Elevated acute phase reactants
    • Positive HLA-B27 (present in 30-50% of patients)
    • Inflammatory synovitis
    • Imaging consistent with enthesitis or arthritis
  • Treatment
    1. Treat any ongoing concurrent infection
    2. NSAIDs (first line)
    3. Steroids (if refractory to NSAIDs)
    4. DMARDS (for chronic reactive arthritis)
    5. Anti-TNF (last resort)
  • Prognosis
    • Duration is typically 3-5 months
    • >6 months duration is considered chronic reactive arthritis
    • Most remit completely or have little active disease w/n 6-12 months after presentation
    • 15-20% may experience more chronic persistent arthritis

Hypothermia and Myxedema Coma – 11/13/18

Thanks to Austin for presenting the case of an elderly woman with h/o psychiatric disorder who presented with acute/subacute onset of AMS, severe hypothermia, sinus bradycardia, and hypotension with work up revealing hypothyroidism suspicious for myxedema coma!


Clinical Pearls

  • Exam findings for hypothermia change depending on severity of hypothermia (see below).
  • It is crucial to measure core body temperature for accuracy especially when you are rewarming the patient (esophageal is the best, rectal/bladder are ok prior to rewarming but can remain low in spite of increasing core body temp so do not rely on these metrics alone)
  • Think of etiologies of hypothermia broadly within the categories of increased loss or decreased heat generation.
  • The most common causes of hypothermia are sepsis, exposure, and hypoglycemia.
  • The hallmarks of myxedema coma are AMS, hypothermia, and a precipitating event (i.e. infection, exposure, meds, etc.)
  • Myxedema coma is a medical emergency with a high mortality rate.  So consult endocrine early when you are suspecting it.
  • Always treat myxedema coma with levothyroxine AND steroids until you have ruled out a concurrent adrenal insufficiency.

HYPOTHERMIA

Types:

  • Mild (32-35°C)
    • Clinical manifestations
      • Shivering, rigors
      • ↑ HR, ↑ RR, ↑ BP, hyperventilation
      • Cold diuresis
        • Body’s attempt to preserve heat.  When peripheral vasoconstriction occurs to keep blood closer to vital organs, BP rises.  Kidneys see this rise in BP and act to correct it by dumping fluid! (Oh kidneys…)
    • Treatment
      • Passive, external
        • Blankets
        • Humidified inspired air
  • Moderate (28-32°C)
    • Clinical manifestations
      • ↓ shivering
      • Confusion, slurred speech
      • ↓ HR, hypoventilation
      • Can also start to notice other cardiac manifestations such as prolonged QTc, QRS, osborn (J) waves, ST elevations/depressions.
      • ↓ renal blood flow
    • Treatment
      • Passive, external (see above) PLUS
      • Active external
        • Forced heated air
        • Warm blankets
        • Warm water immersion
      • Active internal
        • Warm humidified air (42°C)
        • Warm IV fluids (42°C)
        • Body cavity lavage (in trauma patients only)
  • Severe (<28°C)
    • Clinical manifestations
      • NO shivering
      • Edema (due to poor renal blood flow) of extremities and lung
      • ↓ HR, ↓ BP (due to drop in cardiac output), hypoventilation, ventricular arrhythmias
      • Cardiac manifestations more common as with moderate hypothermia
      • AMS
      • Paradoxical undressing
        • mechanism is poorly understood but thought to be due to paralysis of the nerves regular vascular muscle tone leading to vasodilation and sensation of a heat flush which results in the patient wanting to take their clothes off.
    •  Treatment
      • Any of the above (passive external, active external, active internal) and/or
      • Extracorporeal
        • HD
        • ECMO

Etiologies of hypothermia:

Capture

Items in red above are the most common causes of hypothermia.

Lab findings:

  • Less reliable since labs have to be warmed prior to processing
    • ABG is often inaccurate
    • Coagulopathy may be masked
    • Hyperkalemia due to rewarming

Complications of rewarming:

  • Hypotension due to peripheral vasodilation
  • Ileus and urinary retention
  • Worsening coagulopathy
  • Arrhythmias
  • Hyperkalemia
  • Core temperature after-drop (a condition in which cold peripheral blood gets shunted to the core and results in further decline in temperature.  You can avoid this by active internal rewarming like warmed IV fluids)

MYXEDEMA COMA 

Learn all about it from our prior blog post here.

Metastatic… Insulinoma? 11/7/2018

Yonglu presented a middle age man with no medical history presenting with syncope. In the preceding months, he has been having non-specific fatigue, decreased exercise tolerance, dizziness, and diaphoresis. He was found to be hypoglycemic after this syncopal episode, and in the hospital his labs were consistent with hyperinsulinism when he was in a hypoglycemic state. CT revealed diffuse liver masses concerning for HCC, as well as a lesion on his left iliac crest appearing to be an osteosarcoma. He was also found to have a pancreatic mass as well…

Three malignant processes? Octreotide scan revealed increased uptake at these regions, and biopsy of the liver revealed a diagnosis of a neuroendocrine tumor!


Hypoglycemia

When we think about hypoglycemia, its pattern can actually give us a clue.

  • Fasting: Most common
  • Post-prandial: non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), post-bariatric surgery hyperinsulinemic hypoglycemia
  • Both: Insulin autoantibody, insulinoma

hypoglycemic-differential-hypoglycemia-malignancy-diagnosis-original

Source: grepmed


Insulinoma

Epidemiology

  • Rare, not enough data
  • Small cohort: median age 48 years, 77% men
  • MEN Type 1: Younger presentation, 20s

Pathophysiology

  • Pancreatic islet cell origin
  • Generally benign, single vs multiple
  • Rare to be malignant (10%)

Presentation

  • Pattern: fasting hypoglycemia mainly but can be both
  • May have some sympathoadrenal sx i.e. palpitations, diaphoresis (seen in this patient), tremulousness
  • Likes to spread to liver, rarely can have bony mets (~13%)

Whipple’s Triad: Presence of all three demonstrates “true” hypoglycemia

  • Symptoms of hypoglycemia
  • Low plasma glucose at time of symptoms
  • Relief of symptoms when glucose is back to normal

Diagnosis

  • Evidence of inappropriately high serum insulin during episode of hypoglycemia
  • 72 hour fasting plasma glucose test: Supervised fast in order to bring on hypoglycemia in order to evaluate etiology. If pt has underlying hyperinsulinism, 95-99% of the time they will be hypoglycemia within 48 hours of fasting.
    • Blood test is drawn when pt has sx of hypoglycemia
    • Test: Glucose, insulin, proinsulin, and c-peptide level.
    • Normal: suppression of endogenous insulin
    • Abnormal: Inappropriately elevated insulin, pro-insulin, and c-peptide in setting of hypoglycemia.
  • Octreotide scan: Increased uptake seen in tumors of neuroendocrine etiology, more sensitive than US, CT, or MRI for detection of somatostatin receptor positive tumors
  • Evidence of hyperinsulinism
    • Low BHB
    • High insulin level
    • High C-peptide
    • High pro-insulin
  • Chromogranin A: used to help diagnose carcinoid tumors (NET of the digestive tract and lungs). Nowadays carcinoid is generally used to refer to well differentiated NETs originating in the lungs. GI tract tumors are now termed NET.

Management

  • Localized lesion: Surgical resection is curative
  • Hypoglycemia
    • Somatostatin analogy
      • Octreotide: Inhibits growth hormone secretion, can switch to Q-monthly formulation
      • Lanreotide
    • Diazoxide: Diminishes insulin secretion, side effects include hirsutism and edema
  • Radiation therapy: Data also limited in utility but can be consider if evidence of bony mets (which is also rare for NET)
  • Chemo:
    • Minority of NET, namely high-grade, well differentiated with Ki67 index > 20%, are rare and there is no consensus on how to treat these patients. These patients generally respond poorly to platinum/etoposide based regimens used to treat most NETs.
    • Other options: Temozolomide, Sunitinib (RTK inhibitor), Everolimus (mTOR inhibitor)

Helpful table for hypoglycemia work up.

Beta-hydroxybutyrate (BHB) is by product of alternate metabolism (more specifically ketone bodies) in a fasting state, so it can be elevated in setting of prolonged fasting (not just DKA).

Also thanks to Arathi for pointing out that insulin has a negative feedback on this process, hence in a hyperinsulinemic state (despite concurrent hypoglycemia), beta hydroxybutyrate would be very low!

Insulinomas can appear like hypoglycemia secondary to oral glycemic agents, but the key is the oral glycemic agent screen would be positive in the latter case!

IGF-omas can cause s/sx hypoglycemia due to similarity with insulin. Expect IGF2 levels to be elevated in such cases and elevated BHB.

Capture.JPG

Please refer to this helpful review article if you want to know more about NETs!

Also please refer to this paper for a case report on AFP-producing pancreatic NET (AFP elevated in this patient!)

Abdominal Pain Secondary to… Lots of Foreign Bodies 11/6/2018

Our doctor-in-training, Jacqueline, presented a case of a 46yo man with a complicated abdominal surgical history, as well as schizophrenia, who presents with acute onset vague abdominal pain. He could not provide any remarkable history (other than abd pain and losing a bag of coins), and his exam was otherwise benign except for mild diffused abdominal pain…

The mystery was resolved on a radiography.

Picture1


Foreign Body Ingestion

Epidemiology

  • Mostly in kids, peaks 1-2 years of age
  • Adults: Typically, accidental (95% of cases) usually related to fish, chicken bones, or toothpicks. More common in older adults, pts with mental illnesses, intoxicated, or inmates (drug trafficking, packers vs stuffers).
  • Most frequent cause of esophageal obstruction = food bolus on existing stricture

Presentation

  • Asymptomatic
  • Stridor/airway compromise/aspiration
  • Chest pain/abdominal pain
  • Fever, shock (perforation)
  • Hemoptysis, hematemesis

Diagnosis

  • Imaging, clinical history

Management:

  • Will depend on stability, the location, nature of the objects ingested, and progression.
  • Expectant management for most blunt objects, ~ 70-80% of objects will pass by day 4. Consider surgical/endoscopic intervention if failure to progress

Battery

  • Presentation
    • Local necrosis secondary to pressure, electrical current, or caustic chemicals.
    • Ulceration can occur within 2-4 hours
    • Perforation can be seen as early as 4-8 hours
    • VERY IMPORTANT to distinguish between coin batteries (thicker, concentric circles) vs coins (thinner, confluent)!
    • Picture2.jpg
  • Complications
    • Vocal cord paralysis, esophageal perf, stricture, tracheal/esophageal fistula, aspiration pneumonia, mediastinitis, erosions into arteries, gastric hemorrhage, intestinal perf
  • Management
    • Esophagus: Emergent removal
    • Beyond esophagus: Depends, most (89%) will pass within 7 days
      • Surgical/Endoscopic option: consider if co-ingestion of magnets, or if remained in stomach for more than 48 hours.
      • GI symptoms
    • Cylindrical batteries: Relatively harmless and usually pass through GI tract without issues, but if stuck in stomach or esophagus, endoscopic removal is recommended

Magnets

  • Presentation
    • Fistula, perforation, volvulus, obstruction, localized necrosis (pressure)
    • Higher chance of complications if multiple magnets and/or metallic objects were ingested.
    • Can react with metal external of the body and cause injury
  • Complications
    • Localized bowel necrosis, obstruction
  • Management
    • Prompt removal endoscopically if in esophagus or stomach.
    • Beyond stomach: Surgery if symptomatic or failure to progress
    • Single magnet: Expectant management, serial XR, monitor progress, don’t be around anything ferromagnetic

Sharp

  • Presentation
    • High risk of perforation/injury if in esophagus, medical emergency
  • Complications
    • Esophageal perforation
    • Intestinal perforation
  • Management
    • Immediately endoscopic removal if in esophagus
    • Beyond:
      • Stomach/proximal duodenum: still consider urgent endoscopic removal, complication risk varies from as low as 10% to 40%
      • Beyond and failure to progress: Surgical intervention recommended.

Packers vs Stuffers

  • Packers: Carefully PACKING illicit substances into packages, lower chance of leakage (image adapted from Vectortoons.com)
    • Picture3.png
  • Stuffers: Hastily STUFFING illicit substances to hide evidence from law enforcement (image adapted from Family Guy), higher chance of content leakage.
    • Picture4
  • Management:
    • Decontamination:
      • Packers: Whole-bowel irrigation safe and feasible
      • Stuffers: Controversial
    • Symptomatic:
      • Opioid (CNS depression, hypoventilation, pinpoint pupils): IV Naloxone 0.05 in nonapneic patients, 0.2 – 1mg in apneic patients. Larger doses may be required if pt ingested a large amount of heroin.
      • Sympathomimetic (agitation, hypertension, hyperthermia): Symptomatic management, airway monitoring, temperature control. AVOID pure beta blockers. Can consider GI decontamination but consult Poison Control.

If suspecting ingestion of potentially toxic substance, don’t hesitate to call Poison Control!

Picture5

 

 

Endobronchial Tuberculosis 11/5/2018

Sarasa presented a case of a young woman with recently diagnosed pulmonary TB on HREZ presenting with worsening dyspnea and voice changes. Her fiberoptic endoscopy of the upper airway was normal. She was found on CT to have tissue thickening and stranding in the mid/lower trachea as well as a small tracheal diverticula, very suspicious for endobronchial TB!


 

Endobronchial tuberculosis

Definition: TB that involves the tracheobronchial tree

Epidemiology

  • More common among patients with extensive pulmonary TB, especially with cavitary lesions, can occur in 10-40% of patients but less common now with anti-TB therapy.
  • For some reason more likely to occur in women in second to third decades of life.
  • Usually seen in main and upper bronchi, but in 5 % of cases: involves the lower trachea

Pathophysiology

  • Unclear but thought to be by either direct extension of pulmonary disease into the bronchi, spread via infected sputum, or hematogenous/lymphatic spread.

Presentation:

  • Cough, CP, hemoptysis, wheezing (low pitch), fatigue, fever, dyspnea. Can mimic foreign body aspiration, non-resolving pneumonia, or malignancy.
  • Can have significant sputum production, leading to bronchorrhea (> 500mL/day of sputum)
  • Complications: Atelectasis, obstruction, bronchiectasis, tracheal stenosis, fistula, hilar lymph node rupture

Diagnosis: CT and bronchoscopy are methods of choice for dx, with bronch being the most validated for confirming the diagnosis.

  • XR: Can be normal in 10-20% of cases
  • CT: Can demonstrate endobronchial lesions, stenosis (up to 2/3 of patients), or fistulas.
  • Bronchoscopy: able to visualize stenosis and biopsy. Can interview if severe symptomatic stenosis.

Management

  • Same as for other forms of TB but also prevent tracheobronchial stenosis
  • Medical Therapy
    • Intensive Phase: HREZ (aka RIPE) x 2 months
      • R: Rifampin
      • I: Isoniazid
      • P: Pyrazinamide
      • E: Ethambutol
    • Continuation Phase
    • Ex: 2HREZ/4HR = standard regimen, 2 months of HREZ (RIPE), followed by 4 months of isoniazid and Rifampin
  • Specific for endobronchial TB
    • Corticosteroids: Controversial.
      • Shown improvement in outcome (prevention of bronchial compression) in children.
      • Some data on shortening healing time and decrease severity of bronchial stenosis
    • Nebulized INH or streptomycin, mixed data
    • Surgery: Usually indicated for stenosis or stricture. Balloon dilatation, stenting, ablation, resection, cryosurgery.
    • Severe tracheobronchial stenosis sometimes requires pneumonectomy or lobectomy

Laryngeal TB:

Distinctive entity, also more prevalence in younger patients, most commonly presents with dysphonia (96%), odynophagia (25%), and stridor (9%). True vocal cords, epiglottis, and false vocal cords are most commonly involved.


Drug Resistance and TB

Definition:

  • Drug-resistance TB: resistant to one or more anti-TB drugs
  • Mono-resistant: single agent
  • Poly-resistant: resistant to multiple drugs, but susceptible to either INH or rifampin but not both
  • MDR: R to INH and rifampin + others.
  • XDR-TB: Extensively drug resistant TB: resistant to INH, rifampin, fluoroquinolones + either aminoglycosides or capreomycin or both.

1st Line Agents

  • Rifampin
  • Isoniazid
  • Pyrazinamide
  • Ethambutol
  • Streptomycin

2nd Line Agents

  • Fluoroquinolones (Levofloxacin, Moxifloxacin)
  • Injectable: Amikacin, Capromycin, Kanamycin
  • Other: Cycloserine, Linezolid, Ethionamide

Addon Agents/Tertiary

Bedaquiline, Para-aminosalicyclic acid, imipenem, meropenem + Augmentin, thioacetazone.

If suspecting resistant, strategy usually is to add at least 2 additional drugs. Adding single drug inc risk for resistance.

Management of drug-resistant TB:

Tx of MTB PCR will be based on susceptibility data

  • Conventional: 20-26 months treatment, with an intensive phase with at least 5 effective drugs for at least 6 months after negative sputum, followed by a continuation phase of at least 4 drugs for 18-24 months
  • Shorten version for 9-12 months if no extra-pulmonary manifestation and susceptible to quinolones.

Please refer to this informative article on a review of endobronchial TB.

All about PE – 11/1/18

Thanks to Barnie for presenting the case of a middle-aged woman who was admitted with acute onset of SOB, found to have submassive PE.


Clinical Pearls:

  • Risk stratification tools are helpful in estimating the pre-test probability of PE.  The best and most validated is Wells criteria.
    • YEARS items is a newer tool that was studied in an RCT in the Netherlands and found to lower the number of CTPA scans ordered by 14% without a significant impact on rates of missed PE diagnoses.
  • For patients at low risk of PE according to Wells, PERC is useful in ED or outpatient setting to rule out PE without ordering a d-dimer (see graphic below).
  • Age-adjusted d-dimer is age x 10 for patients older than 50 years.  This accounts for the increase in d-dimer baseline related to aging.  ADJUST-PE trial showed that age-adjusted d-dimer leads to higher specificity without subsequent VTE.
    • Studies have shown an 11.6% reduction in CTPA scans with the use of this correction factor without an appreciable increase in missed diagnoses of PE.
  • Think of PE in three broad categories:
    • Massive PE = hemodynamically unstable ⇒ anticoagulation + thrombolysis
    • Submassive PE = hemodynamically stable + RV strain ⇒ anticoagulation + thrombolysis
    • Low risk PE = hemodynamically stable, no RV strain ⇒ anticoagulation.  Use the PESI score to determine if your patient can be treated outpatient.
  • Remember that the most common EKG finding in PE is normal sinus rhythm!  The most common abnormal  EKG finding is sinus tachycardia.  S1Q3T3 pattern is only seen in 10% of patients with PE.

Diagnosis:

Suggested algorithm for diagnostic work up of suspected PE:

PE diagnostics

Remember that the scoring tools above are only there to add to your clinical judgment, not replace it!

Recent study in the Lancet looked at the utility of a different diagnostic algorithm, using the three most predictive items on Wells together with d-dimer.  Compared to Wells, this diagnostic tool led to a 14% reduction in unnecessary CTPA!

PE diagnostics 2

Treatment:

PE treatment.PNG

  • Remember that clot burden does not factor into the treatment categories of PE.  Low clot burden in a patient with baseline cardiopulmonary disease can still lead to hemodynamic compromise and would be considered massive PE.
  • Submassive PE treatment is an area of much debate.  A famous trial (PEITHO trial) in 2014 randomized 1006 patients to receive heparin + placebo vs heparin + tenecteplase (European version), and found a >50% reduction in combined death and cardiovascular collapse at 7 days but a > four-fold increase in risk of major bleed including intracranial hemorrhage.  Subsequent meta-analyses (and this one) found that the risk of major bleeding was highest in people >65 years of age.  So treatment decisions here are tricky and require consulting multiple services!

Signs of RV strain: 

  • EKG findings:
    • S1Q3T3: this is a sign of cor pulmonale and can be seen in a number of conditions in addition to PE
      • Bronchospasm (really bad asthma)
      • ARDS
      • Pneumothorax
  • Echo findings:
    • Elevated RVSP
    • Septal bowing
    • McConnell’s sign (regional wall motion abnormality sparing the RV apex)
      • Not sensitive but helpful in distinguishing RV strain due to chronic pulmonary HTN from RV strain due to acute PE
    • Increased RV size
    • Decreased RV function
    • Tricuspid regurgitation
  • Labs
    • Elevated troponin
    • Elevated BNP

Liver Cirrhosis Secondary to Hemochromatosis and Alcohol (10/30/2018)

Narges presented a case of a late-middle age woman with history of recurrent pancreatitis, chronic alcohol use, who presents with worsening leg swelling, nausea/vomiting, and chest pain in setting of increased alcohol intake from bereavement. She increased her alcohol intake from “several drinks” a day to a fifth of hard liquor per day for the past few weeks. She was incidentally found to have a severely elevated Transferrin Sat, and genetics study revealed HFE mutation consistent with hemochromatosis.


For those of us illiterate in EtOH… A standard drink is defined as:

Capture

Hemochromatosis:

Epidemiology

  • Hereditary: Up to 10% of Caucasians in US and Western Europe are thought to be heterozygous. Homozygous roughly 0.5%.
  • Symptomatic median age around age 40 for males, later for females due to higher iron loss.

Pathophysiology

  • Disorder of iron storage, that results in increased intestinal iron absorption and iron deposition.
  • Iron deposition leads to organ damage.
  • Hereditary form
    • Most commonly secondary to mutant HFE (human hemochromatosis protein).
    • HFE codes a protein involved in cellular iron sensing and intestinal iron absorption regulation.
    • Autosomal recessive with variable penetrance.
    • Heterozygotes are asymptomatic and are not at risk of iron-overload.
    • Homozygous patients have variable disease penetrance, thought to be relatively low.
    • ***Key point: Just because someone has the mutation (can be incidentally found on genetic sequencing) does not mean they will have the disease (iron build up in the body leading to end organ damage).
    • Alcohol intake is a major risk factor for development of liver disease for patients with HFE mutation. Iron overload thought to potentiate effect of alcohol induced liver toxicity
    • Liver damage occurs without inflammation, but hence HH can occur in setting without elevated AST/ALT.
    • At least 43% of HH pts have other underlying causes i.e. fatty liver, alcohol, HBV/HCV, that leads to elevated transaminases and liver cirrhosis.
    • Most common mutant is C282Y, if heterozygous, not at risk for developing progressive or symptomatic iron overload.
    • Homozygous C282Y are at risk but again penetrance is variable.
    • Homozygous H63D are generally not at risk but might have minor abnormalities in iron studies. If symptomatic, usually has other underlying process i.e. alcohol (such as this patient).
  • Secondary iron overload (seen in frequent transfusions due to ineffective erythropoiesis)

Presentation

  • Takes time to develop end-organ damage. Patients are usually asymptomatic until they have 20+ g of iron built up in the body (average iron content of an adult is 4-5g).
  • Early: Non-specific, weakness, weight loss, skin hyperpigmentation (bronze skin), abd pain, loss of libido.
  • Later: Hepatomegaly (95%), cirrhosis, HCC
  • Other organs:
    • DM (50%, pancreas) chronic pancreatitis (advanced hemochromatosis)
    • Hypogonadism (ovaries, testes), impotence/infertility
    • Hypothyroidism (thyroid)
    • Adrenal insufficiency (adrenals)
    • Arthralgia (joints, CPPD pseudogout), osteoporosis (pan hypopit leading to secondary hypogonadism)
    • Heart (heart failure, enlargement)
    • Pan-hypopit (pituitary)

Infection Risk

  • Listeria, Yersinia, and Vibrio sp have increased in an iron rich environment. Mucor sp also favors an iron-rich environment

Diagnosis

  • Labs: Inc Fe, % transferrin sat, and serum ferritin levels.
  • Healthy pt: Fasting serum transferrin sat > 50% is abnormal and possibly suggestive of underlying hemochromatosis.
  • Serum transferrin sat: PPV of 26-39%, 80% if two separate, positive tests. NPV of 100%
  • Ferritin levels: not that useful, acute phase reactant, can fluctuate.

Management

  • Remove excess iron!
  • Intermittent phlebotomy, goal serum iron 50-100mcg/dL
  • 1 unit of blood = 250mg Fe, hence to get 20g of iron town to a relatively normal level via phlebotomy, this might take 2-3 years.
  • Chelating agents: Deferoxamine, less effective compared to weekly phlebotomy strategy but indicated in instances when you cannot do phlebotomy, i.e. anemia.

Prognosis

  • IF caught early, organ damage is reversible with iron removal
  • If cirrhosis has set in, this increases risk of hepatocellular carcinoma by 20-200 fold.

Screening

  • All 1st degree family members of a patient with confirmed hemochromatosis should be screened with a genetics study +/- an iron panel.
  • Per AASLD 2011 Guideline:

Screening